Substituted imidazopyridines, their preparation and their use as pharmaceuticals

ABSTRACT

This application relates to substituted imidazopyridines, compositions comprising them and their uses in the treatment of diseases and conditions in which inhibition of a bromodomain is indicated. For example, the application relates to substituted imidazopyridines and to their use as bromodomain inhibitors. The present application is also related to the treatment or prevention of proliferative disorders, auto-immune disorders, inflammatory disorders, dermal disorders, and neoplasms, including tumors and/or cancers.

TECHNICAL FIELD

The technical field generally compounds, compositions and their uses inthe treatment of diseases and conditions in which inhibition ofbromodomains is indicated. For example, the application relates toimidazopyridines, to pharmaceutical compositions comprising the same,and to their use as bromodomain inhibitors. The present application isalso related to the treatment or prevention of proliferative disorders,auto-immune disorders, inflammatory disorders, dermal disorders, andneoplasms, including tumors and/or cancers.

BACKGROUND

Bromodomains are found in a variety of mammalian DNA-binding proteins.The bromodomain, which is the conserved structural module inchromatin-associated proteins and histone acetyltransferases, is knownto recognize acetyl-lysine residues on proteins. Bromodomain inhibitorsare believed to be useful in the treatment of a variety of diseases orconditions, such as cancer as well as chronic autoimmune andinflammatory conditions. There is therefore a need for compounds thatcould inhibit bromodomains.

SUMMARY

According to one aspect, the present application relates to compounds ofFormula I, and pharmaceutically acceptable salts, solvates, esters orprodrugs thereof:

wherein,

R¹ is a substituted or unsubstituted group selected from C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₃-C₁₀heterocycloalkyl,C₃-C₁₀cycloalkylC₁-C₆alkyl-, C₃-C₁₀heterocycloalkylC₁-C₆alkyl-,C₆-C₁₀arylC₁-C₆alkyl-, C₅-C₁₀heteroarylC₁-C₆alkyl-, C(O)R^(a), OR^(a),NHR^(a), N(R^(a))₂, C(O)NH₂, C(O)NHR^(a), C(O)N(R^(a))₂, NHC(O)R^(a),N(R^(a))C(O)R^(a), NHC(O)NHR^(a), N(R^(a))C(O)NHR^(a), NHC(O)N(R^(a))₂,N(R^(a))C(O)N(R^(a))₂, NHSO₂R^(a), N(R^(a))SO₂R^(a), NHSO₂NHR^(a),N(R^(a))SO₂NHR^(a), NHSO₂N(R^(a))₂, N(R^(a))SO₂N(R^(a))₂, SO₂R^(a),SO₂NH₂, SO₂NHR^(a), and SO₂N(R^(a))₂;

R^(a) is, independently in each occurrence, a substituted orunsubstituted group selected from C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₃-C₁₀heterocycloalkyl,C₃-C₁₀cycloalkylC₁-C₆alkyl-, C₃-C₁₀heterocycloalkylC₁-C₆alkyl-,C₅-C₁₀aryl, C₅-C₁₀heteroaryl, C₆-C₁₀arylC₁-C₆alkyl-, andC₅-C₁₀heteroarylC₁-C₆alkyl-;

R² is selected from H, NH₂, CN or a substituted or unsubstituted groupselected from C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl,C₃-C₁₀heterocycloalkyl, C₆-C₁₀aryl, C₅-C₁₀heteroaryl, C(O)R^(a), OR^(a),SR^(a), NHR^(a), N(R^(a))₂, C(O)NH₂, C(O)NHR^(a), C(O)N(R^(a))₂,NHC(O)R^(a), SO₂R^(a), SO₂NHR^(a), SO₂N(R^(a))₂, NHSO₂R^(a),N(R^(a))SO₂R^(a), NHSO₂NHR^(a), N(R^(a))SO₂NHR^(a), NHSO₂N(R^(a))₂, andN(R^(a))SO₂N(R^(a))₂;

R³ and R⁶ are each independently H, halogen, NH₂, CN or a substituted orunsubstituted group selected from C₁-C₆alkyl, C(O)R^(a), OR^(a),NHR^(a), N(R^(a))₂, C(O)NH₂, C(O)NHR^(a), C(O)N(R^(a))₂, NHC(O)R^(a);and

one of R⁴ and R⁵ is H, halogen, NH₂, CN or a substituted orunsubstituted group selected from C₁-C₆alkyl, C(O)R^(a), NH₂, NHR^(a),N(R^(a))₂, C(O)NH₂, C(O)NHR^(a), C(O)N(R^(a))₂, and NHC(O)R^(a); and theother of R⁴ and R⁵ is a group of Formula II:

wherein,

R⁷ and R¹⁰ are each independently H, halogen (such as F, Cl), CN, or asubstituted or unsubstituted group selected from C₁-C₆alkyl orC₃-C₆cycloalkyl group, OC₁-C₆alkyl, OC₃-C₆cycloalkyl, SC₁-C₆alkyl,SC₃-C₆cycloalkyl, NHC₁-C₆alkyl, NHC₃-C₆cycloalkyl, N(C₁-C₆alkyl)₂,NHC(O)C₁₋C₆alkyl and NHC(O)C₃-C₆cycloalkyl;

R⁸ is halogen (such as F, Cl), CN, or a substituted or unsubstitutedgroup selected from C₁-C₆alkyl or C₃-C₆cycloalkyl group, OC₁-C₆alkyl,OC₃-C₆cycloalkyl, SC₁-C₆alkyl, SC₃-C₆cycloalkyl, NHC₁-C₆alkyl,NHC₃-C₆cycloalkyl, N(C₁-C₆alkyl)₂, NHC(O)C₁-C₆alkyl andNHC(O)C₃-C₆cycloalkyl;

R⁹ is a substituted or unsubstituted C₁-C₃alkyl or C₃-C₅cycloalkylgroup; and

X¹, X², and X³ are each selected from a nitrogen or carbon atom, whereinwhen X¹, X², or X³ is a nitrogen atom, then the R⁷, R⁸, or R¹⁰ attachedthereto is absent, provided that at least two of X¹, X², and X³ are C.

In one embodiment, the compound is of Formula I, wherein R⁴ is a groupof Formula II, preferably wherein said R⁵ is hydrogen or a substitutedor unsubstituted C₁-C₃ alkyl. According to another embodiment, thecompound is of Formula I, wherein R⁵ is a group of Formula II,preferably wherein said R⁴ is hydrogen or a substituted or unsubstitutedC₁-C₃ alkyl.

In one embodiment, in Formula II, groups X¹, X² and X³ are all carbonatoms. In another embodiment, X¹ is a nitrogen atom and R¹⁰ is absent,and X² and X³ are carbon atoms. For instance, the group of Formula IImay be defined as a group of Formula II (a):

wherein R⁷, R⁸, R⁹ and R¹⁰ are as herein defined.

In one embodiment, R⁹ is an unsubstituted C₁-C₃alkyl or C₃-C₅cycloalkylgroup or a fluorinated C₁-C₃alkyl group or C₃-C₅cycloalkyl group, forinstance trifluoromethyl, a methyl, ethyl, n-propyl, isopropyl orcyclopropyl group. In another embodiment, R⁷ and R¹⁰ are each hydrogenatoms and R⁸ is selected from Cl, CN, and a substituted or unsubstitutedC₁-C₃alkyl, C₃cycloalkyl, NHC₁-C₃alkyl, or NH(C₁-C₃alkyl)₂ group.

Another embodiment of the application relates to compounds of FormulaI(a), and pharmaceutically acceptable salts, solvates, esters orprodrugs thereof:

wherein,R¹, R², R³, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are as herein defined.

According to another embodiment, the application also relates tocompounds of Formula I(b), and pharmaceutically acceptable salts,solvates, esters or prodrugs thereof:

wherein,R¹, R², R³, R⁴, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are as herein defined.

In one embodiment, the application relates to compounds as hereindefined wherein R³ is H or a substituted or unsubstituted C₁-C₆alkylgroup, for example, R³ is H. In another embodiment, the applicationrelates to compounds as herein defined wherein R⁶ is H or a substitutedor unsubstituted C₁-C₆alkyl group, for instance, R⁶ is H.

In another embodiment, the present application relates to compounds ofFormula III, and pharmaceutically acceptable salts, solvates, esters orprodrugs thereof:

wherein R¹, R², R⁴ and R⁵ are as herein defined.

Another embodiment of the application relates to compounds of FormulaIII(a), and pharmaceutically acceptable salts, solvates, esters orprodrugs thereof:

wherein R¹, R², R⁷, R⁸, R⁹, and R¹⁰ are as herein defined.

According to another embodiment, the application also relates tocompounds of Formula III(b), and pharmaceutically acceptable salts,solvates, esters or prodrugs thereof:

wherein R¹, R², R⁷, R⁸, R⁹, and R¹⁰ are as herein defined.

According to one embodiment, the application relates to compounds ofFormula III(a) or III(b) as herein defined, wherein R⁹ is anunsubstituted C₁-C₃alkyl or C₃-C₅cycloalkyl group. In anotherembodiment, the application relates to compounds of Formula III(a) orFormula III(b) as herein defined, wherein R⁹ is selected from methyl,trifluoromethyl, ethyl, n-propyl, isopropyl and cyclopropyl. In anotherembodiment, R⁸ and R⁹ are each independently a methyl, ethyl, isopropyl,fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, ordifluorocyclopropyl group

According to another embodiment, the application relates to compounds ofFormula III(a) or III(b) as herein defined, wherein said R⁷ and R¹⁰ areeach hydrogen atoms and R⁸ is selected from Cl, CN, and a substituted orunsubstituted C₁-C₃alkyl, C₃cycloalkyl, NHC₁-C₃alkyl, or NH(C₁-C₃alkyl)₂group.

In yet another embodiment, the present application relates to a compoundof Formula I, I(a), I(b), III, III(a) or III(b) as herein defined,wherein R² is hydrogen or a substituted or unsubstituted group selectedfrom C₁-C₆alkyl, C₃-C₁₀cycloalkyl, or C₃-C₁₀heterocycloalkyl group. Forinstance, R² is a substituted or unsubstituted C₁-C₃alkyl,C₃-C₆cycloalkyl, or C₃-C₆heterocycloalkyl group, or R² is a substitutedor unsubstituted group selected from methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl,tetrahydrofuranyl, tetrahydropyranyl, dioxolanyl, piperidinyl, andpyrrolidinyl, preferably, R² is hydrogen or a substituted orunsubstituted methyl or ethyl group.

In a further embodiment, the present application relates to a compoundof Formula I, I(a), I(b), III, III(a) or III(b) as herein defined,wherein R¹ is a branched or linear C₁-C₆alkyl group, unsubstituted orsubstituted with one or more group(s) selected from halogen, OH, NH₂,CN, or a substituted or unsubstituted group selected fromC₃-C₁₀cycloalkyl, C₃-C₁₀heterocycloalkyl, C₅-C₁₀aryl, C₅-C₁₀heteroaryl,C(O)R^(a), OR^(a), NHR^(a), N(R^(a))₂, C(O)NH₂, C(O)NHR^(a),C(O)N(R^(a))₂, NHC(O)R^(a), N(R^(a))C(O)R^(a), NHC(O)NHR^(a),N(R^(a))C(O)NHR^(a), NHC(O)N(R^(a))₂, N(R^(a))C(O)N(R^(a))₂, NHSO₂R^(a),N(R^(a))SO₂R^(a), NHSO₂NHR^(a), N(R^(a))SO₂NHR^(a), NHSO₂N(R^(a))₂,N(R^(a))SO₂N(R^(a))₂, SO₂R^(a), SO₂NH₂, SO₂NHR^(a), SO₂N(R^(a))₂,wherein R^(a) is as herein defined. In another embodiment, R¹ is abranched or linear C₁-C₃alkyl group, unsubstituted or substituted withone or more group(s) selected from halogen, OH, NH₂, CN, or asubstituted or unsubstituted group selected from C₃-C₁₀cycloalkyl,C₃-C₁₀heterocycloalkyl, C₆-C₁₀aryl, C₅-C₁₀heteroaryl, C(O)R^(a), OR^(a),NHR^(a), N(R^(a))₂, C(O)NH₂, C(O)NHR^(a), C(O)N(R^(a))₂, NHC(O)R^(a),N(R^(a))C(O)R^(a), NHC(O)NHR^(a), N(R^(a))C(O)NHR^(a), NHC(O)N(R^(a))₂,N(R^(a))C(O)N(R^(a))₂, NHSO₂R^(a), N(R^(a))SO₂R^(a), NHSO₂NHR^(a),N(R^(a))SO₂NHR^(a), NHSO₂N(R^(a))₂, N(R^(a))SO₂N(R^(a))₂, SO₂R^(a),SO₂NH₂, SO₂NHR^(a), SO₂N(R^(a))₂, wherein R^(a) is as herein defined. Ina further embodiment, R¹ is a C₁-C₂alkyl substituted with one or moregroup(s) selected from halogen or a substituted or unsubstituted groupselected from C₃-C₁₀cycloalkyl, C₃-C₁₀heterocycloalkyl, C₅-C₁₀aryl,C₅-C₁₀heteroaryl, C(O)R^(a), OR^(a), NHR^(a), N(R^(a))₂, C(O)NH₂,C(O)NHR^(a), C(O)N(R^(a))₂, NHC(O)R^(a), N(R^(a))C(O)R^(a), NHSO₂R^(a),N(R^(a))SO₂R^(a), NHSO₂NHR^(a), N(R^(a))SO₂NHR^(a), NHSO₂N(R^(a))₂,N(R^(a))SO₂N(R^(a))₂, SO₂R^(a), SO₂NH₂, SO₂NHR^(a), SO₂N(R^(a))₂,wherein R^(a) is as herein defined. In yet another embodiment, R¹ is aC₁alkyl substituted with one or more substituted or unsubstituted groupselected from C₃-C₁₀cycloalkyl, C₃-C₁₀heterocycloalkyl, C₆-C₁₀aryl,C₅-C₁₀heteroaryl, OR^(a), and NHR^(a), wherein R^(a) is as hereindefined. In a further embodiment, R¹ is selected from C(O)R^(a), OR^(a),NHR^(a), N(R^(a))₂, C(O)NHR^(a), C(O)N(R^(a))₂, SO₂R^(a), SO₂NHR^(a),and SO₂N(R^(a))₂, wherein R^(a) is as herein defined. In yet anotherembodiment, R¹ is selected from C(O)C₃-C₁₀heterocycloalkyl, OR^(a),NHR^(a), N(R^(a))₂, C(O)NHR^(a), SO₂(C₃-C₁₀heterocycloalkyl), andSO₂NHR^(a), wherein R^(a) is as herein defined.

In one embodiment, R^(a) is, independently in each occurrence, selectedfrom a substituted or unsubstituted C₁-C₆alkyl, C₃-C₁₀cycloalkyl,C₃-C₁₀heterocycloalkyl, C₆-C₁₀aryl, or C₅-C₁₀heteroaryl.

In a further embodiment, this application relates to a compound selectedfrom Compounds 1 to 56 as herein defined, or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof, for instance, any of thesecompounds or their isomers, or a pharmaceutically acceptable salt,solvate, or prodrug thereof, may be taken individually or as sub-groups.

Another aspect related to pharmaceutical composition, comprising acompound as defined in the present application, together with apharmaceutically acceptable carrier, diluent or excipient.

A further aspect relates to the use of a compound as defined in thepresent application, or such a compound for use, in the treatment orprevention of a disease or condition for which a bromodomain inhibitoris indicated. Similarly, this aspect relates to the use of a compound ofthe present application in the manufacture of a medicament for thetreatment or prevention of a disease or condition for which abromodomain inhibitor is indicated. This aspect also further relates toa method for treating a disease or condition for which a bromodomaininhibitor is indicated, which comprises administering to a subject inneed thereof, a therapeutically effective amount of a compound as hereindefined. In one embodiment, the disease or condition for which abromodomain inhibitor is indicated is an auto-immune disorder, aninflammatory disorder (such as rheumatoid arthritis, irritable bowelsyndrome, or psoriasis), a dermal disorder, or cancer (for instance,brain cancer, pancreatic cancer, breast cancer, lung cancer, or prostatecancer). For instance the disease or condition is brain cancer, such asglioblastoma multiforme.

According to a further aspect, the application relates to the use of acompound as herein defined, or such a compound for use, in the treatmentof a disease or condition selected from auto-immune disorders,inflammatory disorders, dermal disorders, and neoplasms. This aspectalso relates to a method for the treatment or prevention of a disease orcondition selected from auto-immune disorders, inflammatory disorders,dermal disorders, and neoplasms, which comprises administering to asubject in need thereof, a therapeutically effective amount of acompound as herein defined. For instance, the inflammatory disorder isrheumatoid arthritis, irritable bowel syndrome, or psoriasis. Forexample, the disease or condition is a neoplasm which is brain cancer(e.g. glioblastoma multiforme), pancreatic cancer, breast cancer, lungcancer, or prostate cancer.

Additional objects and features of the present compounds, compositions,methods and uses will become more apparent upon reading of the followingnon-restrictive description of exemplary embodiments, which should notbe interpreted as limiting the scope of the invention.

DESCRIPTION

All technical and scientific terms used herein have the same meaning ascommonly understood by one ordinary skilled in the art to which thepresent technology pertains. For convenience, the meaning of certainterms and phrases used herein are provided below.

To the extent the definitions of terms in the publications, patents, andpatent applications incorporated herein by reference are contrary to thedefinitions set forth in this specification, the definitions in thisspecification control. The section headings used herein are fororganizational purposes only, and are not to be construed as limitingthe subject matter disclosed.

i. Definitions

The terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting. It should be notedthat, the singular forms “a”, “an”, and “the” include plural forms aswell, unless the content clearly dictates otherwise. Thus, for example,reference to a composition containing “a compound” also contemplates amixture of two or more compounds. It should also be noted that the term“or” is generally employed in its sense including “and/or” unless thecontent clearly dictates otherwise. Furthermore, to the extent that theterms “including”, “includes”, “having”, “has”, “with”, or variantsthereof are used in either the detailed description and/or the claims,such terms are intended to be inclusive in a manner similar to the term“comprising”.

The term “about” or “approximately” means within an acceptable errorrange for the particular value as determined by one of ordinary skill inthe art, which will depend in part on how the value is measured ordetermined, i.e., the limitations of the measurement system. Forexample, “about” can mean within 1 or more than 1 standard deviation,per the practice in the art. Alternatively, “about” can mean a range ofup to 20%, preferably up to 10%, more preferably up to 5%, and morepreferably still up to 1% of a given value. Alternatively, particularlywith respect to biological systems or processes, the term can meanwithin an order of magnitude, preferably within 5-fold, and morepreferably within 2-fold, of a value. Where particular values aredescribed in the application and claims, unless otherwise stated theterm “about” meaning within an acceptable error range for the particularvalue should be assumed.

As used herein, the terms “compounds herein described”, “compounds ofthe present application” and equivalent expressions refer to compoundsdescribed in the present application, e.g., those encompassed bystructural Formulae such as Formula I, I(a), I(b), III, III(a), andIII(b), optionally with reference to any of the applicable embodiments,and also includes exemplary compounds, for example, Compounds 1-56, aswell as their pharmaceutically acceptable salts, solvates, esters, andprodrugs when applicable. When a zwitterionic form is possible, thecompound may be drawn as its neutral form for practical purposes, butthe compound is understood to also include its zwitterionic form.Embodiments herein may also exclude one or more of the compounds.Compounds may be identified either by their chemical structure or theirchemical name. In a case where the chemical structure and chemical namewould conflict, the chemical structure will prevail.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the present description. Unless otherwise stated, all tautomericforms of the compounds are within the scope of the present description.Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of the present description. Such compounds areuseful, for example, as analytical tools, as probes in biologicalassays, or as therapeutic agents in accordance with the presentdescription.

Where a particular enantiomer is preferred, it may, in some embodimentsbe provided substantially free of the corresponding enantiomer, and mayalso be referred to as “optically enriched.” “Optically-enriched,” asused herein, means that the compound is made up of a significantlygreater proportion of one enantiomer. In certain embodiments thecompound is made up of at least about 90% by weight of a preferredenantiomer. In other embodiments the compound is made up of at leastabout 95%, 98%, or 99% by weight of a preferred enantiomer.

Preferred enantiomers may be isolated from racemic mixtures by anymethod known to those skilled in the art, including chiral high pressureliquid chromatography (HPLC) and the formation and crystallization ofchiral salts or prepared by asymmetric syntheses. See, for example,Jacques et al., Enantiomers, Racemates and Resolutions (WileyInterscience, New York, 1981); Wilen, et al., Tetrahedron 33:2725(1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H. Tables of Resolving Agents and OpticalResolutions, p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, NotreDame, Ind. 1972).

Definitions of specific functional groups and chemical terms aredescribed in more detail below. For purposes of the present description,the chemical elements are identified in accordance with the PeriodicTable of the Elements, CAS version, Handbook of Chemistry and Physics,75^(th), Ed., inside cover, and specific functional groups are generallydefined as described therein. Additionally, general principles oforganic chemistry, as well as specific functional moieties andreactivity, are described in Organic Chemistry, Thomas Sorrell,University Science Books, Sausalito, 1999; Smith and March March'sAdvanced Organic Chemistry, 5^(th), Edition, John Wiley & Sons, Inc.,New York, 2001; Larock, Comprehensive Organic Transformations, VCHPublishers, Inc., New York, 1989; Carruthers, Some Modern Methods ofOrganic Synthesis, 3^(rd) Edition, Cambridge University Press,Cambridge, 1987.

The number of carbon atoms in a hydrocarbyl substituent can be indicatedby the prefix “C_(x)-C_(y),” where x is the minimum and y is the maximumnumber of carbon atoms in the substituent. However, when the prefix“C_(x)-C_(y)” is associated with a group incorporating one or moreheteroatom(s) by definition (e.g. heterocycloalkyl, heteroaryl, etc),then x and y define respectively the minimum and maximum number of atomsin the cycle, including carbons as well as heteroatom(s).

The prefix “halo” indicates that the substituent to which the prefix isattached is substituted with one or more independently selected halogenradicals. More specifically, the terms “halo” and “halogen” as usedherein refer to an atom selected from fluorine (fluoro, —F), chlorine(chloro, —Cl), bromine (bromo, —Br), and iodine (iodo, —I). For example,“haloalkyl” means an alkyl substituent wherein at least one hydrogenradical is replaced with a halogen radical.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR+(as in N-substituted pyrrolidinyl).

As used herein a “direct bond” or “covalent bond” refers to a single,double or triple bond. In certain embodiments, a “direct bond” or“covalent bond” refers to a single bond.

Abbreviations may also be used throughout the application, unlessotherwise noted, such abbreviations are intended to have the meaninggenerally understood by the field. Examples of such abbreviationsinclude Me (methyl), Et (ethyl), Pr (propyl), i-Pr (isopropyl), Bu(butyl), t-Bu (tert-butyl), i-Bu (iso-butyl), s-Bu (sec-butyl), c-Bu(cyclobutyl), Ph (phenyl), Bn (benzyl), Bz (benzoyl), CBz or Cbz or Z(carbobenzyloxy), Boc or BOC (tert-butoxycarbonyl), and Su or Suc(succinimide). For greater certainty, examples of abbreviations used inthe present application are listed in a table in the Examples section.

The chemical structures herein are drawn according to the conventionalstandards known in the art. Thus, where an atom, such as a carbon atom,as drawn appears to have an unsatisfied valency, then that valency isassumed to be satisfied by a hydrogen atom even though that hydrogenatom is not necessarily explicitly drawn. Hydrogen atoms should beinferred to be part of the compound.

The term “aliphatic” or “aliphatic group”, as used herein, denotes ahydrocarbon moiety that may be straight-chain (i.e., unbranched),branched, or cyclic (including fused, bridging, and spiro-fusedpolycyclic) and may be completely saturated or may contain one or moreunits of unsaturation, but which is not aromatic. Unless otherwisespecified, aliphatic groups contain 1-6 carbon atoms. In someembodiments, aliphatic groups contain 1-4 carbon atoms, and in yet otherembodiments aliphatic groups contain 1-3 carbon atoms. Aliphatic groupsinclude, but are not limited to, alkyl, alkenyl, alkynyl, carbocycle.Suitable aliphatic groups include, but are not limited to, linear orbranched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof suchas (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term “alkyl” as used herein, refers to a saturated, straight- orbranched-chain hydrocarbon radical typically containing from 1 to 20carbon atoms. For example, “C₁-C₈ alkyl” contains from one to eightcarbon atoms. Examples of alkyl radicals include, but are not limitedto, methyl, ethyl, propyl, isopropyl, w-butyl, tert-butyl, neopentyl,n-hexyl, heptyl, octyl radicals and the like.

The term “alkenyl” as used herein, denotes a straight- or branched-chainhydrocarbon radical containing one or more double bonds and typicallyfrom 2 to 20 carbon atoms. For example, “C₂-C₈ alkenyl” contains fromtwo to eight carbon atoms. Alkenyl groups include, but are not limitedto, for example, ethenyl, propenyl, butenyl, I-methyl-2-buten-1-yl,heptenyl, octenyl and the like.

The term “alkynyl” as used herein, denotes a straight- or branched-chainhydrocarbon radical containing one or more triple bonds and typicallyfrom 2 to 20 carbon atoms. For example, “C₂-C₈ alkynyl” contains fromtwo to eight carbon atoms. Representative alkynyl groups include, butare not limited to, for example, ethynyl, 1-propynyl, 1-butynyl,heptynyl, octynyl and the like.

The terms “cycloalkyl”, “alicyclic”, “carbocyclic” and equivalentexpressions refer to a group comprising a saturated or partiallyunsaturated (non aromatic) carbocyclic ring in a monocyclic orpolycyclic ring system, including spiro (sharing one atom), fused(sharing at least one bond) or bridged (sharing two or more bonds)carbocyclic ring systems, having from three to fifteen ring members.Examples of cycloalkyl groups include, without limitation, cyclopropyl,cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclopenten-2-yl,cyclopenten-3-yl, cyclohexyl, cyclohexen-1-yl, cyclohexen-2-yl,cyclohexen-3-yl, cycloheptyl, bicyclo[4,3,0]nonanyl, norbornyl, and thelike. The term cycloalkyl includes both unsubstituted cycloalkyl groupsand substituted cycloalkyl groups. The term “C₃-C_(n)cycloalkyl” refersto a cycloalkyl group having from 3 to the indicated “n” number ofcarbon atoms in the ring structure. Unless the number of carbons isotherwise specified, “lower cycloalkyl” groups as herein used, have atleast 3 and equal or less than 8 carbon atoms in their ring structure.

As used herein, the terms “heterocycle”, “heterocycloalkyl”,“heterocyclyl”, “heterocyclic radical”, and “heterocyclic ring” are usedinterchangeably and refer to a chemically stable 3- to 7-memberedmonocyclic or 7-10-membered bicyclic heterocyclic moiety that is eithersaturated or partially unsaturated, and having, in addition to carbonatoms, one or more, preferably one to four, heteroatoms, as definedabove. When used in reference to a ring atom of a heterocycle, the term“nitrogen” includes a substituted nitrogen. As an example, in asaturated or partially unsaturated ring having 1-3 heteroatoms selectedfrom oxygen, sulfur or nitrogen, the nitrogen may be N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or +NR (as inN-substituted pyrrolidinyl). A heterocyclic ring can be attached to itspendant group at any heteroatom or carbon atom that results in achemically stable structure and any of the ring atoms can be optionallysubstituted. Examples of heterocycloalkyl groups include, but are notlimited to, 1,3-dioxolanyl, pyrrolidinyl, pyrrolidonyl, pyrazolinyl,pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl,oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl,isothiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydrothiopyranyl, tetrahydrodithienyl, tetrahydrothienyl,thiomorpholino, thioxanyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl,2H-pyranyl, 4H-pyranyl, dioxanyl, dithianyl, dithiolanyl,dihydropyranyl, dihydrothienyl, dihydrofuranyl,3-azabicyclo[3,1,0]hexanyl, 3-azabicyclo[4,1,0]heptanyl, quinolizinyl,quinuclidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, and the like. Heterocyclic groups also includegroups in which a heterocyclic ring is fused to one or more aryl,heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl,chromanyl, chromenyl, phenanthridinyl, 2-azabicyclo[2.2.1]heptanyl,octahydroindolyl, or tetrahydroquinolinyl, where the radical or point ofattachment is on the heterocyclyl ring. A heterocyclyl group may bemono- or bicyclic. The term “heterocyclylalkyl” refers to an alkyl groupsubstituted by a heterocyclyl, wherein the alkyl and heterocyclylportions independently are optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond between ring atoms butis not aromatic. The term “partially unsaturated” is intended toencompass rings having multiple sites of unsaturation, but is notintended to include aryl or heteroaryl moieties, as herein defined.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to a monocyclic moietyor to a bicyclic or tricyclic fused ring system having a total of six to15 ring members, wherein at least one ring in the system is aromatic andwherein each ring in the system contains three to seven ring members.The term “aryl” may be used interchangeably with the term “aryl ring”.In certain embodiments of the present description, “aryl” refers to anaromatic ring system which includes, but not limited to, phenyl,biphenyl, naphthyl, azulenyl, anthracyl and the like, which may bear oneor more substituents. The term “aralkyl” or “arylalkyl” refers to analkyl residue attached to an aryl ring. Examples of aralkyl include, butare not limited to, benzyl, phenethyl, 1-phenylethyl, and the like. Alsoincluded within the scope of the term “aryl”, as it is used herein, is agroup in which an aromatic ring is fused to one or more non-aromaticrings, such as indanyl, indenyl, phthalimidyl, naphthimidyl, fluorenyl,phenanthridinyl, or tetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-”, used alone or as part of alarger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer togroups having 5 to 18 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. The term“heteroatom” includes but is not limited to nitrogen, oxygen, or sulfur,and includes any oxidized form of nitrogen or sulfur, and anyquaternized form of a basic nitrogen. A heteroaryl may be a single ring,or two or more fused rings. Heteroaryl groups include, withoutlimitation, thienyl, furanyl (furyl), thienyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl,thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, furopyridinyl, indolizinyl, purinyl,naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”,as used herein, also include groups in which a heteroaromatic ring isfused to one or more aryl, cycloaliphatic, or heterocyclyl rings, wherethe radical or point of attachment is on the heteroaromatic ring.Nonlimiting examples include indolyl, 3H-indolyl, isoindolyl,benzothienyl (benzothiophenyl), benzofuranyl, dibenzofuranyl, indazolyl,benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolyl (quinolinyl),isoquinolyl (isoquinolinyl), quinolonyl, isoquinolonyl, cinnolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl,acridinyl, phenanthridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, andpyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group may be mono- orbicyclic. Heteroaryl groups include rings that are optionallysubstituted. The term “heteroaralkyl” refers to an alkyl groupsubstituted by a heteroaryl, wherein the alkyl and heteroaryl portionsindependently are optionally substituted. Examples include, but are notlimited to, pyridinylmethyl, pyrimidinylethyl and the like.

The term “bivalent hydrocarbon” refers to a bivalent saturated orunsaturated hydrocarbon group. Such bivalent hydrocarbon groups includealkylene, alkenylene, and alkynylene groups.

The term “alkylene” refers to a divalent group derived from a straightor branched saturated hydrocarbyl chain typically containing from 1 to20 carbon atoms, more typically from 1 to 8 carbon atoms. Examples of an“alkylene” include a polymethylene group, i.e., —(CH₂)n-, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3; or —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—,and —CH₂CH(CH₃)CH₂—. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a divalent unsaturated hydrocarbyl groupwhich may be linear or branched and which has at least one carbon-carbondouble bond. An alkenylene group typically contains 2 to 20 carbonatoms, more typically from 2 to 8 carbon atoms. Non-limiting examples ofalkenylene groups include —C(H)═C(H)—, —C(H)═C(H)—CH₂—,—C(H)═C(H)—CH₂—CH₂—, —CH₂—C(H)═C(H)—CH₂—, —C(H)═C(H)—CH(CH₃)—, and—CH₂—C(H)═C(H)—CH(CH₂CH₃)—.

The term “alkynylene” refers to a divalent unsaturated hydrocarbon groupwhich may be linear or branched and which has at least one carbon-carbontriple bond. Examples of alkynylene groups include, without limitation,—C≡C—, —C≡C—CH₂—, —C≡C—CH₂—CH₂—, —CH₂—C≡C—CH₂—, —C≡C—CH(CH₃)—, and—CH₂—C≡C—CH(CH₂CH₃)—.

As described herein, compounds of the present description may contain“optionally substituted” moieties. In general, the term “substituted”,whether preceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at eachposition. Combinations of substituents envisioned under the presentdescription are preferably those that result in the formation ofchemically stable or chemically feasible compounds. The term “chemicallystable”, as used herein, refers to compounds that are not substantiallyaltered when subjected to conditions to allow for their production,detection, and, in certain embodiments, their recovery, purification,and use for one or more of the purposes disclosed herein.

The terms “optionally substituted”, “optionally substituted alkyl,”“optionally substituted alkenyl,” “optionally substituted alkynyl”,“optionally substituted carbocyclic,” “optionally substituted aryl”,“optionally substituted heteroaryl,” “optionally substitutedheterocyclic,” and any other optionally substituted group as usedherein, refer to groups that are substituted or unsubstituted byindependent replacement of one, two, or three or more of the hydrogenatoms thereon with substituents including, but not limited to F, Cl, Br,I, OH, CO₂H, alkoxy, oxo, thiooxo, NO₂, CN, CF₃, NH₂, protected amino,NHalkyl, NHalkenyl, NHalkynyl, NHcycloalkyl, NHaryl, NHheteroaryl,NHheterocyclic, dialkylamino, diarylamino, diheteroarylamino, O-alkyl,O-alkenyl, O-alkynyl, O-cycloalkyl, O-aryl, O-heteroaryl, O-haloalkyl,O-heterocyclic, C(O)alkyl, C(O)alkenyl, C(O)alkynyl, C(O)cycloalkyl,C(O)aryl, C(O)heteroaryl, C(O)heterocycloalkyl, CO₂alkyl, CO₂alkenyl,CO₂alkynyl, CO₂cycloalkyl, CO₂aryl, CO₂heteroaryl, CO₂heterocycloalkyl,OC(O)alkyl, OC(O)alkenyl, OC(O)alkynyl, OC(O)cycloalkyl, OC(O)aryl,OC(O)heteroaryl, OC(O)heterocycloalkyl, C(O)NH₂, C(O)NHalkyl,C(O)NHalkenyl, C(O)NHalkynyl, C(O)NHcycloalkyl, C(O)NHaryl,C(O)NHheteroaryl, C(O)NHheterocycloalkyl, OCO₂alkyl, OCO₂alkenyl,OCO₂alkynyl, OCO₂cycloalkyl, OCO₂aryl, OCO₂heteroaryl,OCO₂heterocycloalkyl, OC(O)NH₂, OC(O)NHalkyl, OC(O)NHalkenyl,OC(O)NHalkynyl, OC(O)NHcycloalkyl, OC(O)NHaryl, OC(O)NHheteroaryl,OC(O)NHheterocycloalkyl, NHC(O)alkyl, NHC(O)alkenyl, NHC(O)alkynyl,NHC(O)cycloalkyl, NHC(O)aryl, NHC(O)heteroaryl, NHC(O)heterocycloalkyl,NHCO₂alkyl, NHCO₂alkenyl, NHCO₂alkynyl, NHCO₂cycloalkyl, NHCO₂aryl,NHCO₂heteroaryl, NHCO₂heterocycloalkyl, NHC(O)NH₂, NHC(O)NHalkyl,NHC(O)NHalkenyl, NHC(O)NHalkenyl, NHC(O)NHcycloalkyl, NHC(O)NHaryl,NHC(O)NHheteroaryl, NHC(O)NHheterocycloalkyl, NHC(S)NH₂, NHC(S)NHalkyl,NHC(S)NHalkenyl, NHC(S)NHalkynyl, NHC(S)NHcycloalkyl, NHC(S)NHaryl,NHC(S)NHheteroaryl, NHC(S)NHheterocycloalkyl, NHC(NH)NH₂,NHC(NH)NHalkyl, NHC(NH)NHalkenyl, NHC(NH)NHalkenyl, NHC(NH)NHcycloalkyl,NHC(NH)NHaryl, NHC(NH)NHheteroaryl, NHC(NH)NHheterocycloalkyl,NHC(NH)alkyl, NHC(NH)alkenyl, NHC(NH)alkenyl, NHC(NH)cycloalkyl,NHC(NH)aryl, NHC(NH)heteroaryl, NHC(NH)heterocycloalkyl, C(NH)NHalkyl,C(NH)NHalkenyl, C(NH)NHalkynyl, C(NH)NHcycloalkyl, C(NH)NHaryl,C(NH)NHheteroaryl, C(NH)NHheterocycloalkyl, S(O)alkyl, S(O)alkenyl,S(O)alkynyl, S(O)cycloalkyl, S(O)aryl, S(O)₂alkyl, S(O)₂alkenyl,S(O)₂alkynyl, S(O)₂cycloalkyl, S(O)₂aryl, S(O)heteroaryl,S(O)heterocycloalkyl, SO₂NH₂, SO₂NHalkyl, SO₂NHalkenyl, SO₂NHalkynyl,SO₂NHcycloalkyl, SO₂NHaryl, SO₂NHheteroaryl, SO₂NHheterocycloalkyl,NHSO₂alkyl, NHSO₂alkenyl, NHSO₂alkynyl, NHSO₂cycloalkyl, NHSO₂aryl,NHSO₂heteroaryl, NHSO₂heterocycloalkyl, CH₂NH₂, CH₂SO₂CH₃, alkyl,alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, cycloalkyl, carbocyclic, heterocyclic,polyalkoxyalkyl, polyalkoxy, methoxymethoxy, methoxyethoxy, SH, S-alkyl,S-alkenyl, S-alkynyl, S-cycloalkyl, S-aryl, S-heteroaryl,S-heterocycloalkyl, or methylthiomethyl.

In certain embodiments, suitable monovalent substituents on asubstitutable carbon atom of an “optionally substituted” group areindependently halogen; (CH₂)₀₋₄R^(o); (CH₂)₀₋₄OR^(o);O(CH₂)₀₋₄C(O)OR^(o); (CH₂)₀₋₄CH(OR^(o))₂; (CH₂)₀₋₄SR^(o); (CH₂)₀₋₄Ph,which may be substituted with R^(o); (CH₂)₀₋₄O(CH₂)₀₋₄Ph which may besubstituted with R^(o); —CH═CHPh, which may be substituted with R^(o);NO₂; CN; N₃; (CH₂)₀₋₄N(R^(o))₂; (CH₂)₀₋₄N(R^(o))C(O)R^(o);N(R^(o))C(S)R^(o); (CH₂)₀₋₄N(R^(o))C(O)NR₂; N(R^(o))C(S)NR^(o) ₂;(CH₂)₀₋₄N(R^(o))C(O)OR^(o); N(R^(o))N(R^(o))C(O)R^(o);N(R^(o))N(R^(o))C(O)NR^(o) ₂; N(R^(o))N(R^(o))C(O)OR^(o);(CH₂)₀₋₄C(O)R^(o); C(S)R^(o); (CH₂)₀₋₄C(O)OR^(o); (CH₂)₀₋₄C(O)SR^(o);(CH₂)₀₋₄C(O)OSiR₃; (CH₂)₀₋₄OC(O)R^(o); OC(O)(CH₂)₀₋₄SR^(o), SC(S)SR^(o);(CH₂)₀₋₄SC(O)R^(o); (CH₂)₀₋₄C(O)NR^(o) ₂; C(S)NR^(o) ₂; C(S)SR^(o);SC(S)SR^(o), (CH₂)₀₋₄OC(O)NR^(o) ₂; C(O)N(OR^(o))R^(o); C(O)C(O)R^(o);C(O)CH₂C(O)R^(o); C(NOR^(o))R^(o); (CH₂)₀₋₄SSR^(o); (CH₂)₀₋₄S(O)₂R^(o);(CH₂)₀₋₄(O)₂OR^(o); (CH₂)₀₋₄OS(O)₂R^(o); S(O)₂NR^(o) ₂;(CH₂)₀₋₄S(O)R^(o); N(R^(o))S(O)₂NR^(o) ₂; N(R^(o))S(O)₂R^(o);N(OR^(o))R^(o); C(NH)NR^(o) ₂; P(O)₂R^(o); P(O)R^(o) ₂; OP(O)R^(o) ₂;OP(O)(OR^(o))₂; SiR^(o) ₃; (straight or branchedC₁₋₄alkylene)O—N(R^(o))₂; or (straight or branchedC₁₋₄alkylene)C(O)O—N(R^(o))₂, wherein each R^(o) may be substituted asdefined below and is independently hydrogen, C₁₋₆aliphatic, CH₂Ph,O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraromatic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or, notwithstanding the definition above,two independent occurrences of R^(o), taken together with theirintervening atom(s), may form a 3 to 12 membered saturated, partiallyunsaturated, or aryl mono- or bicyclic ring having 0 to 4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, which may besubstituted as defined below.

Examples of monovalent substituents on R^(o) (or the ring formed bytaking two independent occurrences of R^(o) together with theirintervening atoms), are independently halogen, —(CH₂)₀₋₂R*, -(haloR*),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR*, —(CH₂)₀₋₂CH(OR*)₂, —O(haloR*), —CN, —N₃,—(CH₂)₀₋₂C(O)R*, —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR*, —(CH₂)₀₋₂SR*,—(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR*, —(CH₂)₀₋₂NR*₂, —NO₂, —SiR*₃,—OSiR*₃, —C(O)SR*—(C₁₋₄straight or branched alkylene)C(O)OR*, or —SSR*,wherein each R* is unsubstituted or where preceded by “halo” issubstituted only with one or more halogens, and is independentlyselected from C₁₋₄ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. Suitabledivalent substituents on a saturated carbon atom of R^(o) include ═O and═S.

Examples of divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃₀—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR₂)₂₋₃₀—, wherein each independent occurrence of R isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Exemplary substituents on the aliphatic group of R* include halogen,—R*, -(haloR*), —OH, —OR*, —O(haloR′), —CN, —C(O)OH, —C(O)OR*, —NH₂,—NHR*, —NR*₂, or —NO₂, wherein each R* is unsubstituted or wherepreceded by “halo” is substituted only with one or more halogens, and isindependently C₁₋₄ aliphatic, —CH₂Ph, —O(CH₂)_(0.1)Ph, or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

The expression “pharmaceutically acceptable salt” refers to those saltsof the compounds formed by the process of the present description whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds of thepresent description, or separately by reacting a free base function ofthe compound with a suitable organic or inorganic acid (acid additionsalts) or by reacting an acidic function of the compound with a suitableorganic or inorganic base (base-addition salts). Examples ofpharmaceutically acceptable salts include, but are not limited to,nontoxic acid addition salts, or salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include, but are notlimited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate,benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate,citrate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate,gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Representative base addition alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, or magnesium salts, and thelike. Further pharmaceutically acceptable salts include, whenappropriate, nontoxic ammonium, quaternary ammonium, and amine cationsformed using counterions such as halide, hydroxide, carboxylate,sulfate, phosphate, nitrate, sulfonate and aryl sulfonate.

The term “solvate” refers to a physical association of one of thepresent compounds with one or more solvent molecules. This physicalassociation includes hydrogen bonding. In certain instances, the solvatewill be capable of isolation, for example when one or more solventmolecules are incorporated in the crystal lattice of a crystallinesolid. “Solvate” encompasses both solution-phase and isolable solvates.Exemplary solvates include, without limitation, hydrates, hemihydrates,ethanolates, hemiethanolates, n-propanolates, iso-propanolates,1-butanolates, 2-butanolate, and solvates of other physiologicallyacceptable solvents, such as the Clas 3 solvents described in theInternational Conference on Harmonization (ICH), Guide for Industry, Q3CImpurities: Residual Solvents (1997). The compounds as herein describedalso include each of their solvates and mixtures thereof.

As used herein, the term “pharmaceutically acceptable ester” refers toesters of the compounds formed by the process of the present descriptionwhich hydrolyze in vivo and include those that break down readily in thehuman body to leave the parent compound or a salt thereof. Suitableester groups include, for example, those derived from pharmaceuticallyacceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic,cycloalkanoic and alkanedioic acids, in which each alkyl or alkenylmoiety advantageously has not more than 6 carbon atoms. Examples ofparticular esters include, but are not limited to, formates, acetates,propionates, butyrates, acrylates and ethylsuccinates.

The expression “pharmaceutically acceptable prodrugs” as used hereinrefers to those prodrugs of the compounds formed by the process of thepresent description which are, within the scope of sound medicaljudgment, suitable for use in contact with the tissues of humans andlower animals with undue toxicity, irritation, allergic response, andthe like, commensurate with a reasonable benefit/risk ratio, andeffective for their intended use. “Prodrug”, as used herein means acompound which is convertible in vivo by metabolic means (e.g. byhydrolysis) to afford any compound delineated by the formulae of theinstantdescription. Various forms of prodrugs are known in the art, forexample, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier(1985); Widder, et al. (ed.), Methods in Enzymoloqy, vol. 4, AcademicPress (1985); Krogsgaard-Larsen, et al., (ed). “Design and Applicationof Prodrugs, Textbook of Drug Design and Development”, Chapter 5,113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews,8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq.(1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug DeliverySystems, American Chemical Society (1975); and Bernard Testa & JoachimMayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry,Biochemistry And Enzymology”, John Wiley and Sons, Ltd. (2002).

Combinations of substituents and variables envisioned by the presentdescription are only those that result in the formation of stablecompounds. The term “stable”, as used herein, refers to compounds whichpossess stability sufficient to allow manufacture and which maintainsthe integrity of the compound for a sufficient period of time to beuseful for the purposes detailed herein (e.g., therapeutic orprophylactic administration to a subject).

ii. Compounds

The compounds of the present application may be prepared by conventionalchemical synthesis, such as exemplified in Schemes 1 to 3 and inExamples 1 to 40. As can be appreciated by the skilled artisan, furthermethods of synthesizing the compounds of the formulae herein will beevident to those of ordinary skill in the art. Additionally, the varioussynthetic steps may be performed in an alternate sequence or order togive the desired compounds. In addition, the solvents, temperatures,reaction durations, etc. delineated herein are for purposes ofillustration only and one of ordinary skill in the art will recognizethat variation of the reaction conditions can produce the desiredproducts of the present description. Synthetic chemistry transformationsand protecting group methodologies (protection and deprotection) usefulin synthesizing the compounds described herein are known in the art andinclude, for example, those such as described in R. Larock,Comprehensive Organic Transformations, VCH Publishers (1989); T. W.Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed.,John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser'sReagents for Organic Synthesis, John Wiley and Sons (1994); and L.Paquette, ed., Encyclopedia of Reaqents for Organic Synthesis, JohnWiley and Sons (1995), and subsequent editions thereof. The synthesizedcompounds can be separated from a reaction mixture and further purifiedby standard methods such as column chromatography, high pressure liquidchromatography, or recrystallization.

The compounds of the present description may be modified by appendingvarious functionalities via any synthetic means delineated herein toenhance selective biological properties. Such modifications are known inthe art and include those which increase biological penetration into agiven biological system (e.g., blood, lymphatic system, central nervoussystem), increase oral availability, increase solubility to allowadministration by injection, alter metabolism and alter rate ofexcretion.

The recitation of a listing of chemical groups in any definition of avariable herein includes definitions of that variable as any singlegroup or combination of listed groups. The recitation of an embodimentfor a variable herein includes that embodiment as any single embodimentor in combination with any other embodiments or portions thereof. Therecitation of an embodiment herein includes that embodiment as anysingle embodiment or in combination with any other embodiments orportions thereof. As such, the following embodiments are present aloneor in combination if applicable:

The present application relates to substituted imidazopyridine compoundsof general Formula I, as well as to their pharmaceutically acceptablesalts, solvates, esters or prodrugs thereof:

wherein,

R¹ is a substituted or unsubstituted group selected from C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₃-C₁₀heterocycloalkyl,C₃-C₁₀cycloalkylC₁-C₆alkyl-, C₃-C₁₀heterocycloalkylC₁-C₆alkyl-,C₆-C₁₀arylC₁-C₆alkyl-, C₅-C₁₀heteroarylC₁-C₆alkyl-, C(O)R^(a), OR^(a),NHR^(a), N(R^(a))₂, C(O)NH₂, C(O)NHR^(a), C(O)N(R^(a))₂, NHC(O)R^(a),N(R^(a))C(O)R^(a), NHC(O)NHR^(a), N(R^(a))C(O)NHR^(a), NHC(O)N(R^(a))₂,N(R^(a))C(O)N(R^(a))₂, NHSO₂R^(a), N(R^(a))SO₂R^(a), NHSO₂NHR^(a),N(R^(a))SO₂NHR^(a), NHSO₂N(R^(a))₂, N(R^(a))SO₂N(R^(a))₂, SO₂R^(a),SO₂NH₂, SO₂NHR^(a), and SO₂N(R^(a))₂; R^(a) is, independently in eachoccurrence, a substituted or unsubstituted group selected fromC₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl,C₃-C₁₀heterocycloalkyl, C₃-C₁₀cycloalkylC₁-C₆alkyl-,C₃-C₁₀heterocycloalkylC₁-C₆alkyl-, C₆-C₁₀aryl, C₅-C₁₀heteroaryl,C₆-C₁₀arylC₁-C₆alkyl-, and C₅-C₁₀heteroarylC₁-C₆alkyl-;

R² is selected from H, NH₂, CN or a substituted or unsubstituted groupselected from C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl,C₃-C₁₀heterocycloalkyl, C₆-C₁₀aryl, C₅-C₁₀heteroaryl, C(O)R^(a), OR^(a),SR^(a), NHR^(a), N(R^(a))₂, C(O)NH₂, C(O)NHR^(a), C(O)N(R^(a))₂,NHC(O)R^(a), SO₂R^(a), SO₂NHR^(a), SO₂N(R^(a))₂, NHSO₂R^(a),N(R^(a))SO₂R^(a), NHSO₂NHR^(a), N(R^(a))SO₂NHR^(a), NHSO₂N(R^(a))₂, andN(R^(a))SO₂N(R^(a))₂;

R³ and R⁶ are each independently H, halogen, NH₂, CN or a substituted orunsubstituted group selected from C₁-C₆alkyl, C(O)R^(a), OR^(a),NHR^(a), N(R^(a))₂, C(O)NH₂, C(O)NHR^(a), C(O)N(R^(a))₂, andNHC(O)R^(a); and

one of R⁴ and R⁵ is H, halogen, NH₂, CN or a substituted orunsubstituted group selected from C₁-C₆alkyl, C(O)R^(a), NH₂, NHR^(a),N(R^(a))₂, C(O)NH₂, C(O)NHR^(a), C(O)N(R^(a))₂, and NHC(O)R^(a); and theother of R⁴ and R⁵ is a group of Formula II:

wherein,

R⁷ and R¹⁰ are each independently H, halogen (such as F, Cl), CN, or asubstituted or unsubstituted group selected from C₁-C₆alkyl orC₃-C₆cycloalkyl group, OC₁-C₆alkyl, OC₃-C₆cycloalkyl, SC₁-C₆alkyl,SC₃-C₆cycloalkyl, NHC₁-C₆alkyl, NHC₃-C₆cycloalkyl, N(C₁-C₆alkyl)₂,NHC(O)C₁-C₆alkyl and NHC(O)C₃-C₆cycloalkyl;

R⁸ is halogen (such as F, Cl), CN, or a substituted or unsubstitutedgroup selected from C₁-C₆alkyl or C₃-C₆cycloalkyl group, OC₁-C₆alkyl,OC₃-C₆cycloalkyl, SC₁-C₆alkyl, SC₃-C₆cycloalkyl, NHC₁-C₆alkyl,NHC₃-C₆cycloalkyl, N(C₁-C₆alkyl)₂, NHC(O)C₁-C₆alkyl andNHC(O)C₃-C₆cycloalkyl;

R⁹ is a substituted or unsubstituted C₁-C₆alkyl or C₃-C₅cycloalkylgroup; and X¹, X², and X³ are each a nitrogen or carbon atom, whereinwhen X¹, X², or X³ is a nitrogen atom, then the R⁷, R⁸, or R¹⁰ attachedthereto is absent, provided that at least two of X¹, X², and X³ are C.

In one embodiment, the compound is of Formula I, wherein R⁴ is a groupof Formula II, preferably wherein said R⁵ is hydrogen or a substitutedor unsubstituted C₁-C₃ alkyl. According to another embodiment, thecompound is of Formula I, wherein R⁵ is a group of Formula II,preferably wherein said R⁴ is hydrogen or a substituted or unsubstitutedC₁-C₃ alkyl.

In one embodiment, in Formula II, X¹ is a nitrogen atom and R¹⁰ isabsent, and X² and X³ are carbon atoms. In another embodiment, X¹, X²and X³ are all carbon atoms. For instance, the group of Formula II maybe defined as a group of Formula II (a):

wherein R⁷, R⁸, R⁹ and R¹⁰ are as herein defined.

In one embodiment, R⁹ is an unsubstituted C₁-C₃alkyl or C₃-C₅cycloalkylgroup or a fluorinated C₁-C₃alkyl group or C₃-C₅cycloalkyl group, forinstance trifluoromethyl, a methyl, ethyl, n-propyl, isopropyl orcyclopropyl group. In another embodiment, R⁷ and R¹⁰ are each hydrogenatoms and R⁸ is selected from Cl, CN, and a substituted or unsubstitutedC₁-C₃alkyl, C₃cycloalkyl, NHC₁-C₃alkyl, or NH(C₁-C₃alkyl)₂ group.

Another embodiment of the application relates to compounds of FormulaI(a), and pharmaceutically acceptable salts, solvates, esters orprodrugs thereof:

wherein,R¹, R², R³, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are as herein defined.

According to another embodiment, the application also relates tocompounds of Formula I(b), and pharmaceutically acceptable salts,solvates, esters or prodrugs thereof:

wherein,R¹, R², R³, R⁴, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are as herein defined.

In one embodiment, the application relates to compounds as hereindefined wherein R³ is H or a substituted or unsubstituted C₁-C₆alkylgroup, e.g. R³ is H. In another embodiment, the application relates tocompounds as herein defined wherein R⁶ is H or a substituted orunsubstituted C₁-C₆alkyl group, e.g. R⁶ is H.

In another embodiment, the present application relates to compounds ofFormula III, and pharmaceutically acceptable salts, solvates, esters orprodrugs thereof:

wherein R¹, R², R⁴ and R⁵ are as herein defined.

Another embodiment of the application relates to compounds of FormulaIII(a), and pharmaceutically acceptable salts, solvates, esters orprodrugs thereof:

wherein R¹, R², R⁷, R⁸, R⁹, and R¹⁰ are as herein defined;or to compounds of Formula III(b), and pharmaceutically acceptablesalts, solvates, esters or prodrugs thereof:

wherein R¹, R², R⁷, R⁸, R⁹, and R¹⁰ are as herein defined.

According to one embodiment, the application relates to compounds ofFormula III(a) or III(b) as herein defined, wherein R⁹ is anunsubstituted C₁-C₃alkyl or C₃-C₅cycloalkyl group. In anotherembodiment, the application relates to compounds of Formula III(a) orFormula III(b) as herein defined, wherein R⁹ is selected from methyl,trifluoromethyl, ethyl, n-propyl, isopropyl and cyclopropyl. In anotherembodiment, R⁸ and R⁹ are each independently a methyl, ethyl, isopropyl,fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, ordifluorocyclopropyl group According to another embodiment, theapplication relates to compounds of Formula III(a) or III(b) as hereindefined, wherein said R⁷ and R¹⁰ are each hydrogen atoms and R⁸ isselected from Cl, CN, and a substituted or unsubstituted C₁-C₃alkyl,C₃cycloalkyl, NHC₁-C₃alkyl, or NH(C₁-C₃alkyl)₂ group.

In one aspect, the present application relates to a compound of FormulaI, I(a), I(b), III, III(a) or III(b) as herein defined in combinationwith any of the described embodiments or subgroup thereof, wherein R² ishydrogen or a substituted or unsubstituted group selected fromC₁-C₆alkyl, C₃-C₁₀cycloalkyl, or C₃-C₁₀heterocycloalkyl group. Forinstance, R² is a substituted or unsubstituted C₁-C₃alkyl,C₃-C₆cycloalkyl, or C₃-C₆heterocycloalkyl group, or R² is a substitutedor unsubstituted group selected from methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl,tetrahydrofuranyl, tetrahydropyranyl, dioxolanyl, piperidinyl, andpyrrolidinyl, preferably, R² is hydrogen or a substituted orunsubstituted methyl or ethyl group.

According to a further aspect, the present application relates to acompound of Formula I, I(a), I(b), III, III(a) or III(b) in combinationwith any of the described embodiments or subgroups thereof, wherein R¹is a branched or linear C₁-C₆alkyl group, unsubstituted or substitutedwith one or more group(s) selected from halogen, OH, NH₂, CN, or asubstituted or unsubstituted group selected from C₃-C₁₀cycloalkyl,C₃-C₁₀heterocycloalkyl, C₆-C₁₀aryl, C₅-C₁₀heteroaryl, C(O)R^(a), OR^(a),NHR^(a), N(R^(a))₂, C(O)NH₂, C(O)NHR^(a), C(O)N(R^(a))₂, NHC(O)R^(a),N(R^(a))C(O)R^(a), NHC(O)NHR^(a), N(R^(a))C(O)NHR^(a), NHC(O)N(R^(a))₂,N(R^(a))C(O)N(R^(a))₂, NHSO₂R^(a), N(R^(a))SO₂R^(a), NHSO₂NHR^(a),N(R^(a))SO₂NHR^(a), NHSO₂N(R^(a))₂, N(R^(a))SO₂N(R^(a))₂, SO₂R^(a),SO₂NH₂, SO₂NHR^(a), SO₂N(R^(a))₂, wherein R^(a) is as herein defined. Inanother embodiment, R¹ is a branched or linear C₁-C₃alkyl group,unsubstituted or substituted with one or more group(s) selected fromhalogen, OH, NH₂, CN, or a substituted or unsubstituted group selectedfrom C₃-C₁₀cycloalkyl, C₃-C₁₀heterocycloalkyl, C₆-C₁₀aryl,C₅-C₁₀heteroaryl, C(O)R^(a), OR^(a), NHR^(a), N(R^(a))₂, C(O)NH₂,C(O)NHR^(a), C(O)N(R^(a))₂, NHC(O)R^(a), N(R^(a))C(O)R^(a),NHC(O)NHR^(a), N(R^(a))C(O)NHR^(a), NHC(O)N(R^(a))₂,N(R^(a))C(O)N(R^(a))₂, NHSO₂R^(a), N(R^(a))SO₂R^(a), NHSO₂NHR^(a),N(R^(a))SO₂NHR^(a), NHSO₂N(R^(a))₂, N(R^(a))SO₂N(R^(a))₂, SO₂R^(a),SO₂NH₂, SO₂NHR^(a), SO₂N(R^(a))₂, wherein R^(a) is as herein defined. Ina further embodiment, R¹ is a C₁-C₂alkyl substituted with one or moregroup(s) selected from halogen or a substituted or unsubstituted groupselected from C₃-C₁₀cycloalkyl, C₃-C₁₀heterocycloalkyl, C₆-C₁₀aryl,C₅-C₁₀heteroaryl, C(O)R^(a), OR^(a), NHR^(a), N(R^(a))₂, C(O)NH₂,C(O)NHR^(a), C(O)N(R^(a))₂, NHC(O)R^(a), N(R^(a))C(O)R^(a), NHSO₂R^(a),N(R^(a))SO₂R^(a), NHSO₂NHR^(a), N(R^(a))SO₂NHR^(a), NHSO₂N(R^(a))₂,N(R^(a))SO₂N(R^(a))₂, SO₂R^(a), SO₂NH₂, SO₂NHR^(a), SO₂N(R^(a))₂,wherein R^(a) is as herein defined. In yet another embodiment, R¹ is aC₁alkyl substituted with one or more substituted or unsubstituted groupselected from C₃-C₁₀cycloalkyl, C₃-C₁₀heterocycloalkyl, C₆-C₁₀aryl,C₅-C₁₀heteroaryl, OR^(a), and NHR^(a), wherein R^(a) is as hereindefined. In a further embodiment, R¹ is selected from C(O)R^(a), OR^(a),NHR^(a), N(R^(a))₂, C(O)NHR^(a), C(O)N(R^(a))₂, SO₂R^(a, SO) ₂NHR^(a),and SO₂N(R^(a))₂, wherein R^(a) is as herein defined. In yet anotherembodiment, R¹ is selected from C(O)C₃-C₁₀heterocycloalkyl, OR^(a),NHR^(a), N(R^(a))₂, C(O)NHR^(a), SO₂(C₃-C₁₀heterocycloalkyl), andSO₂NHR^(a), wherein R^(a) is as herein defined.

In an alternative definition, R¹ is represented as a R^(a) group linkedto the imidazopyridine bicyclic core via a linker, wherein said linkeris selected from a linear or branched —C₁-C₃akyl-, —C₁-C₃akylO—,—OC₁-C₃akyl-, —C₁-C₃akylN(H)—, —NHC₁-C₃akyl-, —C₁-C₃akylN(R^(a))—,—NR^(a)C₁-C₃akyl-, C(O), O, NH, —N(R^(a))—, —C(O)N(H)—, —C(O)N(R^(a))—,SO₂, —SO₂N(H)—, and —SO₂N(R^(a))— group.

In one embodiment, R^(a) is, independently in each occurrence, selectedfrom a substituted or unsubstituted C₁-C₆alkyl, C₃-C₁₀cycloalkyl,C₃-C₁₀heterocycloalkyl, C₃-C₁₀aryl, or C₅-C₁₀heteroaryl. In oneembodiment, R^(a) is, when within the definition of R¹, aC₃-C₁₀cycloalkyl, C₃-C₁₀heterocycloalkyl, C₆-C₁₀aryl, orC₅-C₁₀heteroaryl group.

Examples of compounds of the present application include, withoutlimitation:

or a pharmaceutically acceptable salt, solvate, ester or prodrugthereof.

In a further embodiment, this application relates to a compound selectedfrom Compounds 1 to 56 as herein defined, or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof, for instance, any of thesecompounds or their isomers, or a pharmaceutically acceptable salt,solvate, or prodrug thereof, may be taken individually or as sub-groups.

iii. Methods, Uses, Formulations and Administration

As used herein, the term “effective amount” means that amount of a drugor pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal or human that is being sought, forinstance, by a researcher or clinician. Furthermore, the term“therapeutically effective amount” means any amount which, as comparedto a corresponding subject who has not received such amount, results intreatment, healing, prevention, or amelioration of a disease, disorder,or side effect, or a decrease in the rate of advancement of a disease ordisorder. The term also includes within its scope amounts effective toenhance normal physiological function.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment may be administeredafter one or more symptoms have developed. In other embodiments,treatment may be administered in the absence of symptoms. For example,treatment may be administered to a susceptible individual prior to theonset of symptoms (e.g., in light of a history of symptoms and/or inlight of genetic or other susceptibility factors). Treatment may also becontinued after symptoms have resolved, for example to prevent or delaytheir recurrence.

As used herein, the term “bromodomain inhibitor” denotes a compoundwhich inhibits the binding of a bromodomain with its cognate acetylatedproteins. In one embodiment the bromodomain inhibitor is a compoundwhich inhibits the binding of a bromodomain to acetylated lysineresidues. In a further embodiment the bromodomain inhibitor is acompound which inhibits the binding of a bromodomain to acetylatedlysine residues on histones, particularly histones H3 and H4.

In a particular embodiment the bromodomain inhibitor is a compound thatinhibits the binding of BET family bromodomains to acetylated lysineresidues (hereafter referred to as a “BET family bromodomaininhibitor”). The BET family of bromodomain containing proteins comprises4 proteins (BRD2, BRD3, BRD4 and BRD-t) which contain tandembromodomains capable of binding to two acetylated lysine residues inclose proximity, increasing the specificity of the interaction.

As used herein, the term “inhibitor” is defined as a compound that bindsto and/or inhibits the target bromodomain-containing protein (such as aBET protein, e.g., BRD2, BRD3, BRD4, and/or BRDT) with measurableaffinity.

The terms “measurable affinity” and “measurably inhibit,” as usedherein, means a measurable change in activity of at least onebromodomain-containing protein between a sample comprising a providedcompound, or composition thereof, and at least one histonemethyltransferase, and an equivalent sample comprising at least onebromodomain-containing protein, in the absence of said compound, orcomposition thereof.

The term “patient or subject” as used herein refers to a mammal. Asubject therefore refers to, for example, dogs, cats, horses, cows,pigs, guinea pigs, and the like. Preferably the subject is a human. Whenthe subject is a human, the subject may be either a patient or a healthyhuman.

In some embodiments, the disease or condition can be an auto-immunedisorder, an inflammatory disorder, a dermal disorder, or cancer. Insome optional embodiments, the disease or condition can be anauto-immune disorder. In some other optional embodiments, the disease orcondition can be an inflammatory disorder. In further optionalembodiments, the inflammatory disorder can be rheumatoid arthritis,irritable bowel syndrome, or psoriasis.

In some other optional embodiments, the disease or condition can becancer. In further optional embodiments, the cancer can be brain cancer,pancreatic cancer, breast cancer, lung cancer, or prostate cancer. Infurther optional embodiments, the cancer can be brain cancer. In furtheroptional embodiments, the brain cancer is glioblastoma multiforme.

In some embodiments, the cancer is selected from the group consistingof: brain (gliomas), glioblastomas, leukemias, lymphomas,Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease,breast, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma,Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, gastric, bladder,head and neck, kidney, lung, liver, melanoma, renal, ovarian,pancreatic, prostate, sarcoma, osteosarcoma, giant cell tumor of boneand thyroid.

In some embodiments, the disorder can be a proliferative disorder,inflammatory disease, sepsis, autoimmune disease, or viral infection. Insome optional embodiments, the proliferative disorder can be cancer.

The term “proliferative disorder” refers to cells having the capacityfor autonomous growth, i.e., an abnormal state of conditioncharacterized by rapidly proliferating cell growth which generally formsa distinct mass that show partial or total lack of structuralorganization and functional coordination with normal tissue.

The terms “neoplasm”, “neoplastic disorder”, “neoplasia” “cancer,” and“tumor” are meant to encompass hematopoietic neoplasms (e.g. lymphomasor leukemias) as well as solid neoplasms (e.g. sarcomas or carcinomas),including all types of pre-cancerous and cancerous growths, or oncogenicprocesses, metastatic tissues or malignantly transformed cells, tissues,or organs, irrespective of histopathologic type or stage ofinvasiveness. Hematopoietic neoplasms are malignant tumors affectinghematopoietic structures (structures pertaining to the formation ofblood cells) and components of the immune system, including leukemias(related to leukocytes (white blood cells) and their precursors in theblood and bone marrow) arising from myeloid, lymphoid or erythroidlineages, and lymphomas (related to lymphocytes). Solid neoplasmsinclude sarcomas, which are malignant neoplasms that originate fromconnective tissues such as muscle, cartilage, blood vessels, fibroustissue, fat or bone. Solid neoplasms also include carcinomas, which aremalignant neoplasms arising from epithelial structures, includingexternal epithelia (e.g., skin and linings of the gastrointestinaltract, lungs, and cervix), and internal epithelia that line variousglands (e.g., breast, pancreas, thyroid). Examples of neoplasms includeleukemia, and hepatocellular cancers, sarcoma, vascular endothelialcancers, breast cancers, central nervous system cancers (e.g.astrocytoma, gliosarcoma, neuroblastoma, oligodendroglioma andglioblastoma), prostate cancers, lung and bronchus cancers, larynxcancers, esophagus cancers, colon cancers, colorectal cancers,gastro-intestinal cancers, melanomas, ovarian and endometrial cancer,renal and bladder cancer, liver cancer, endocrine cancer (e.g. thyroid),and pancreatic cancer.

In some aspects, examples of cancers treated using the compounds andmethods described herein include, but are not limited to, acinic cellcarcinoma, acoustic neuroma, acral lentiginous melanoma, acrospiroma,acute eosinophilic leukemia, acute erythroid leukemia, acutelymphoblastic leukemia, acute lymphocytic leukemia, acutemegakaryoblastic leukemia, acute monocytic leukemia, acute myelogenousleukemia, acute myelognous leukemia, acute promyelocytic leukemia,adrenal cancer, adenocarcinoma, adenoid cystic carcinoma, adenoma,adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissueneoplasm, adrenal cancer, adrenocortical carcinoma, adult T-cellleukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma,alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblasticfibroma, anaplastic large cell lymphoma, anaplastic thyroid cancer,angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma,astrocytoma, atypical teratoid rhabdoid tumor, Bannayan-Zonana syndrome,basal cell carcinoma, B-cell chronic lymphocytic leukemia, B-celllymphoma, B-cell prolymphocytic leukemia, biliary tract cancer, bladder,bladder cancer, blastoma, bone cancer, brain (gliomas), brain cancer,breast, breast cancer, Brenner tumor, Brown tumor, Burkitt's lymphoma,carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor,cementoma, cervical cancer, chondroma, chordoma, choriocarcinoma,choroid plexus papilloma, chronic lymphocytic leukemia, clear-cellsarcoma of the kidney, colon, colorectal cancer, Cowden disease,craniopharyngioma, cutaneous T-cell lymphoma, Degos disease,desmoplastic small round cell tumor, diffuse large B-cell lymphoma,dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonalcarcinoma, endocrine gland neoplasm, endodermal sinus tumor,enteropathy-associated T-cell lymphoma, ependymoma, esophageal cancer,Ewing's sarcoma, fetus in fetu, fibroma, fibrosarcoma, follicularlymphoma, follicular thyroid cancer, gallbladder cancer, ganglioneuroma,gastric, gastric cancer, gastrointestinal cancer, germ cell tumor,gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumorof bone and thyroid, giant cell tumor of the bone, glial tumor,glioblastoma multiforme, glioblastomas, glioma, gliomatosis cerebri,glucagonoma, gonadoblastoma, granulosa cell tumor, gynandroblastoma,hairy cell leukemia, head and neck, head and neck cancer,hemangioblastoma, hemangiopericytoma, hematological malignancy,hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma,inflammatory breast cancer, intestinal cancer, invasive lobularcarcinoma, kidney, kidney cancer, laryngeal cancer, lentigo maligna,lethal midline carcinoma, leukemia, leukemias, leydig cell tumor,Lhermitte-Duclos disease, liposarcoma, liver, liver cancer, lung, lungcancer, lymphangio sarcoma, lymphangioma, lymphoepithelioma, lymphoma,lymphomas, malignant fibrous histiocytoma, malignant peripheral nervesheath tumor, malignant triton tumor, MALT lymphoma, mantle celllymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinalgerm cell tumor, medullary carcinoma of the breast, medullary thyroidcancer, medulloblastoma, melanoma, meningioma, merkel cell cancer,mesothelioma, metastatic urothelial carcinoma, mixed Mullerian tumor,mucinous tumor, multiple myeloma, muscle tissue neoplasm, mycosisfungoides, myeloid sarcoma, myxoid liposarcoma, myxoma, myxosarcoma,nasopharyngeal carcinoma, neurinoma, neuroblastoma, neurofibroma,neuroma, nodular melanoma, non-Hodgkin's lymphoma, non-small cell lungcancer, ocular cancer, oligoastrocytoma, oligodendroglioma, oncocytoma,optic nerve sheath meningioma, optic nerve tumor, oral cancer,osteosarcoma, ovarian, ovarian cancer, Pancoast tumor, pancreatic,pancreatic cancer, papillary thyroid cancer, paraganglioma, pharyngealcancer, pinealoblastoma, pineocytoma, pituicytoma, pituitary adenoma,pituitary tumor, plasmacytoma, polyembryoma, precursor T-lymphoblasticlymphoma, primary central nervous system lymphoma, primary effusionlymphoma, primary peritoneal cancer, prostate, prostate cancer,pseudomyxoma peritonei, rectal cancer, renal, renal cell carcinoma,renal medullary carcinoma, retinoblastoma, rhabdomyoma,Rhabdomyosarcoma, Richter's transformation, sarcoma, Schwannomatosis,seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, Sezary'sdisease, signet ring cell carcinoma, skin cancer, small blue round celltumors, small cell carcinoma, small cell lung cancer, small intestinecancer, soft tissue sarcoma, somatostatinoma, soot wart, spinal tumor,splenic marginal zone lymphoma, squamous carcinoma, squamous cellcarcinoma, stomach cancer, synovial sarcoma, T-cell lymphoma, testicularcancer, thecoma, throat cancer, thyroid cancer, transitional cellcarcinoma, urachal cancer, urogenital cancer, urothelial carcinoma,uterine cancer, uveal melanoma, vaginal cancer, verrucous carcinoma,visual pathway glioma, vulvar cancer, Waldenstrom's macroglobulinemia,Warthin's tumor, and Wilm's tumor.

In some embodiments, the cancer can be adenocarcinoma, adult T-cellleukemia/lymphoma, bladder cancer, blastoma, bone cancer, breast cancer,brain cancer, carcinoma, myeloid sarcoma, cervical cancer, colorectalcancer, esophageal cancer, gastrointestinal cancer, glioblastomamultiforme, glioma, gallbladder cancer, gastric cancer, head and neckcancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, intestinal cancer,kidney cancer, laryngeal cancer, leukemia, lung cancer, lymphoma, livercancer, small cell lung cancer, non-small cell lung cancer,mesothelioma, multiple myeloma, ocular cancer, optic nerve tumor, oralcancer, ovarian cancer, pituitary tumor, primary central nervous systemlymphoma, prostate cancer, pancreatic cancer, pharyngeal cancer, renalcell carcinoma, rectal cancer, sarcoma, skin cancer, spinal tumor, smallintestine cancer, stomach cancer, T-cell lymphoma, testicular cancer,thyroid cancer, throat cancer, urogenital cancer, urothelial carcinoma,uterine cancer, vaginal cancer, or Wilms' tumor. In some otherembodiments, the cancer can be acute myelognous leukemia or Burkitt'slymphoma.

In some embodiments, the autoimmune and inflammatory diseases orconditions can involve an inflammatory response to infections withbacteria, viruses, fungi, parasites or their toxins, as well as viruses.In some other embodiments, the autoimmune and inflammatory diseases orconditions can be selected from the group consisting of acute lunginjury, acute pancreatitis, acute renal failure, ARDS (adult respiratorydistress syndrome), burns, coronavirus, encephalitis, endotoxaemia,fulminant hepatitis, herpes simplex, herpes zoster, Herxheimerreactions, malaria and SIRS associated with viral infections such asinfluenza, meningitis, multi-organ dysfunction syndrome, myelitis,post-surgical syndromes, sarcoidosis, sepsis, sepsis syndrome, septicshock, systemic inflammatory response syndrome (SIRS), toxic shocksyndrome.

In some embodiments, the present description provides a method oftreating other conditions. Such other conditions include, but are notlimited to, acne, acute inflammatory responses (such as acuterespiratory distress syndrome and ischemia/reperfusion injury,glioblastoma, Graves' disease, HIV, HPV, inflammatory disease, keloidsand related scarring, lung cancer, meningitis (bacterial and viral),multiple sclerosis, neoplasm, neuroblastoma, pancreatic cancer,scleroderma, skin cancer, toxic shock, viral infections, viralinfections and diseases.

In some embodiments, the present description provides a method oftreating a benign proliferative disorder. Such benign proliferativedisorders include, but are not limited to, benign soft tissue tumors,bone tumors, brain and spinal tumors, eyelid and orbital tumors,granuloma, lipoma, meningioma, multiple endocrine neoplasia, nasalpolyps, pituitary tumors, prolactinoma, pseudotumor cerebri, seborrheickeratoses, stomach polyps, thyroid nodules, cystic neoplasms of thepancreas, hemangiomas, vocal cord nodules, polyps, and cysts, Castlemandisease, chronic pilonidal disease, dermatofibroma, pilar cyst,prolactinoma, pseudotumor cerebri, pyogenic granuloma, and juvenilepolyposis syndrome.

The present description further relates to a method for treatinginfectious and noninfectious inflammatory events and autoimmune andother inflammatory diseases by administration of an effective amount ofa provided compound to a mammal, in particular a human in need of suchtreatment. Examples of autoimmune and inflammatory diseases, disorders,and syndromes treated using the compounds and methods described hereininclude inflammatory pelvic disease, urethritis, skin sunburn,sinusitis, pneumonitis, encephalitis, meningitis, myocarditis,nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis,dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis,agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowelsyndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection,hyperacute rejection of transplanted organs, asthma, allergic rhinitis,chronic obstructive pulmonary disease (COPD), autoimmune polyglandulardisease (also known as autoimmune polyglandular syndrome), autoimmunealopecia, pernicious anemia, glomerulonephritis, dermatomyositis,multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic andthrombocytopenic states, Goodpasture's syndrome, atherosclerosis,Addison's disease, Parkinson's disease, Alzheimer's disease, Type Idiabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoidarthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis,chronic idiopathic thrombocytopenic purpura, Waldenstrommacroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopicdermatitis, degenerative joint disease, vitiligo, autoimmunehypopituitarism, Guillain-Barre syndrome, Behcet's disease,scleracierma, mycosis fungoides, acute inflammatory responses (such asacute respiratory distress syndrome and ischemia/reperfusion injury),and Graves' disease. Other examples of infectious and noninfectiousinflammatory events, autoimmune and other inflammatory diseases include,but are not limited to, Addison's disease, agammaglobulinemia, allergicrhinitis, allergy, Alzheimer's disease, appendicitis, asthma,atherosclerosis, atopic dermatitis, autoimmune alopecia, autoimmunehemolytic and thrombocytopenic states, autoimmune hypopituitarism,autoimmune polyglandular disease (also known as autoimmune polyglandularsyndrome), Behcet's disease, cholecystitis, chronic idiopathicthrombocytopenic purpura, chronic obstructive pulmonary disease (COPD),Crohn's disease, degenerative joint disease, dermatitis,dermatomyositis, encephalitis, enteritis, gastritis, gingivitis,glomerulonephritis, Goodpasture's syndrome, Guillain-Barre syndrome,Hashimoto's thyroiditis, hepatitis, hyperacute rejection of transplantedorgans, inflammatory pelvic disease, irritable bowel syndrome, juvenilearthritis, meningitis, multiple sclerosis, myasthenia gravis, mycosisfungoides, myocarditis, myositis, nephritis, osteoarthritis,osteomyelitis, pancreatitis, Parkinson's disease, pernicious anemia,pneumonitis, psoriasis, psoriatic arthritis, rheumatoid arthritis,scleracierma, scleroderma, septic shock, sinusitis, Sjogren's disease,skin sunburn, systemic lupus erythematosus (SLE), tissue graftrejection, Type I diabetes, ulcerative colitis, urethritis, vasculitis,vitiligo, and Waldenstrom macroglobulinemia.

In some embodiments, the present description provides a method oftreating systemic inflammatory response syndromes such as LPS-inducedendotoxic shock and/or bacteria-induced sepsis by administration of aneffective amount of a provided compound to a mammal, in particular ahuman in need of such treatment.

The present description further relates to a method for treating viralinfections and diseases by administration of an effective amount of aprovided compound to a mammal, in particular a human in need of suchtreatment. Examples of viral infections and diseases treated using thecompounds and methods described herein include episome-based DNA virusesincluding, but not limited to, human papillomavirus, Herpesvirus,Epstein-Barr virus, human immunodeficiency virus, hepatis B virus, andhepatitis C virus.

The present description further relates to a method of treating asubject, such as a human, suffering from one of the abovementionedconditions, illnesses, disorders or diseases. The method comprisesadministering a therapeutically effective amount of one or more providedcompounds, which function by inhibiting a bromodomain and, in general,by modulating gene expression, to induce various cellular effects, inparticular induction or repression of gene expression, arresting cellproliferation, inducing cell differentiation and/or inducing apoptosis,to a subject in need of such treatment.

The present description further provides a therapeutic method ofmodulating protein methylation, gene expression, cell proliferation,cell differentiation and/or apoptosis in vivo in diseases mentionedabove, in particular cancer, inflammatory disease, and/or viral diseasecomprising administering to a subject in need of such therapy apharmacologically active and therapeutically effective amount of one ormore provided compounds.

The present description further provides a method of regulatingendogenous or heterologous promoter activity by contacting a cell with aprovided compound.

In certain embodiments, the present description provides a method oftreating a disorder (as described herein) in a subject, comprisingadministering to the subject identified as in need thereof, a compoundof the present description. The identification of those patients who arein need of treatment for the disorders described above is well withinthe ability and knowledge of one skilled in the art. Certain of themethods for identification of patients which are at risk of developingthe above disorders which can be treated by the subject method areappreciated in the medical arts, such as family history, and thepresence of risk factors associated with the development of that diseasestate in the subject patient. A clinician skilled in the art can readilyidentify such candidate patients, by the use of, for example, clinicaltests, physical examination and medical/family history.

A method of assessing the efficacy of a treatment in a subject includesdetermining the pre-treatment extent of a disorder by methods well knownin the art (e.g., determining tumor size or screening for tumor markerswhere the cell proliferative disorder is cancer) and then administeringa therapeutically effective amount of a compound of the presentdescription, to the subject. After an appropriate period of time afterthe administration of the compound (e.g., 1 day, 1 week, 2 weeks, onemonth, six months), the extent of the disorder is determined again. Themodulation (e.g., decrease) of the extent or invasiveness of thedisorder indicates efficacy of the treatment. The extent or invasivenessof the disorder may be determined periodically throughout treatment. Forexample, the extent or invasiveness of the disorder may be checked everyfew hours, days or weeks to assess the further efficacy of thetreatment. A decrease in extent or invasiveness of the disorderindicates that the treatment is efficacious. The method described may beused to screen or select patients that may benefit from treatment with acompound of the present description.

According to one aspect, there is provided a method for identifyingcompounds for use in treating autoimmune and inflammatory diseases orconditions which comprises the step of determining whether the compoundinhibits the binding of a bromodomain with its cognate acetylatedprotein.

According to another embodiment, the description provides a method ofinhibiting a bromodomain-containing protein (such as a BET protein,e.g., BRD2, BRD3, BRD4, and/or BRDT) using a composition comprising acompound of the present description or a pharmaceutically acceptablederivative thereof and a pharmaceutically acceptable carrier, adjuvant,or vehicle. The amount of a compound of the present description in aprovided composition is such that is effective to measurably inhibit oneor more bromodomain-containing proteins (such as a BET protein, e.g.,BRD2, BRD3, BRD4, and/or BRDT), or a mutant thereof, in a biologicalsample or in a patient. In certain embodiments, the amount of compoundin a provided composition is such that is effective to measurablyinhibit one or more bromodomain-containing proteins (such as a BETprotein, e.g., BRD2, BRD3, BRD4, and/or BRDT), or a mutant thereof, in abiological sample or in a patient. In certain embodiments, a providedcomposition is formulated for administration to a patient in need ofsuch composition. In some embodiments, a provided composition isformulated for oral administration to a patient.

In some embodiments, the therapeutically effective amount of a compoundas defined herein can be administered to a patient alone or admixed witha pharmaceutically acceptable carrier, adjuvant, or vehicle.

The expression “pharmaceutically acceptable carrier, adjuvant, orvehicle” and equivalent expressions, refer to a non-toxic carrier,adjuvant, or vehicle that does not destroy the pharmacological activityof the compound with which it is formulated. Pharmaceutically acceptablecarriers, adjuvants or vehicles that may be used in the compositions ofthis disclosure include, but are not limited to, ion exchangers,alumina, aluminum stearate, lecithin, serum proteins, such as humanserum albumin, buffer substances such as phosphates, glycine, sorbicacid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

A “pharmaceutically acceptable derivative” means any non-toxic salt,ester, salt of an ester, prodrug, salt of a prodrug, or other derivativeof a compound of the present description that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of the present description or an inhibitory active metaboliteor residue thereof.

As used herein, the term “inhibitory active metabolite or residuethereof” means that a metabolite or residue thereof is also an inhibitorof one or more bromodomain-containing protein(s) (such as a BET protein,e.g., BRD2, BRD3, BRD4, and/or BRDT), or a mutant thereof.

Compositions described herein may be administered orally, parenterally,by inhalation spray, topically, rectally, nasally, buccally, vaginallyor via an implanted reservoir. The term “parenteral” as used hereinincludes subcutaneous, intravenous, intramuscular, intraarticular,intrasynovial, intrasternal, intrathecal, intrahepatic, intralesionaland intracranial injection or infusion techniques. Other modes ofadministration also include intradermal or transdermal administration.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a provided compound, it is oftendesirable to slow the absorption of the compound from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the compound then depends upon itsrate of dissolution that, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered compound form is accomplished by dissolving or suspendingthe compound in an oil vehicle. Injectable depot forms are made byforming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled.

Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the compound in liposomes or microemulsions that arecompatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thepresent description with suitable non-irritating excipients or carrierssuch as cocoa butter, polyethylene glycol or a suppository wax which aresolid at ambient temperature but liquid at body temperature andtherefore melt in the rectum or vaginal cavity and release the activecompound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone(PVP), sucrose, and acacia, c) humectants such as glycerol, d)disintegrating agents such as agar-agar, calcium carbonate, potato ortapioca starch, alginic acid, certain silicates, and sodium carbonate,e) solution retarding agents such as paraffin, f) absorptionaccelerators such as quaternary ammonium compounds, g) wetting agentssuch as, for example, cetyl alcohol and glycerol monostearate, h)absorbents such as kaolin and bentonite clay, and i) lubricants such astalc, calcium stearate, magnesium stearate, solid polyethylene glycols,sodium lauryl sulfate, and mixtures thereof. In the case of capsules,tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

Provided compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch.

Such dosage forms may also comprise, as is normal practice, additionalsubstances other than inert diluents, e.g., tableting lubricants andother tableting aids such a magnesium stearate and microcrystallinecellulose. In the case of capsules, tablets and pills, the dosage formsmay also comprise buffering agents. They may optionally containopacifying agents and can also be of a composition that they release theactive ingredient(s) only, or preferentially, in a certain part of theintestinal tract, optionally, in a delayed manner. Examples of embeddingcompositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthe present description include ointments, pastes, creams, lotions,gels, powders, solutions, sprays, inhalants or patches.

The active component is admixed under sterile conditions with apharmaceutically acceptable carrier and any needed preservatives orbuffers as may be required. Ophthalmic formulation, ear drops, and eyedrops are also contemplated as being within the scope of the presentdescription.

Additionally, the description contemplates the use of transdermalpatches, which have the added advantage of providing controlled deliveryof a compound to the body. Such dosage forms can be made by dissolvingor dispensing the compound in the proper medium. Absorption enhancerscan also be used to increase the flux of the compound across the skin.The rate can be controlled by either providing a rate controllingmembrane or by dispersing the compound in a polymer matrix or gel.

Pharmaceutically acceptable compositions provided herein may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promotors to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Pharmaceutically acceptable compositions provided herein may beformulated for oral administration. Such formulations may beadministered with or without food. In some embodiments, pharmaceuticallyacceptable compositions of this disclosure are administered withoutfood. In other embodiments, pharmaceutically acceptable compositions ofthis disclosure are administered with food.

The amount of provided compounds that may be combined with carriermaterials to produce a composition in a single dosage form will varydepending upon the patient to be treated and the particular mode ofadministration. Provided compositions may be formulate such that adosage of between 0.01-100 mg/kg body weight/day of the inhibitor can beadministered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including age, body weight, general health, sex, diet, time ofadministration, rate of excretion, drug combination, the judgment of thetreating physician, and the severity of the particular disease beingtreated. The amount of a provided compound in the composition will alsodepend upon the particular compound in the composition. Compounds orcompositions described herein may be administered using any amount andany route of administration effective for treating or lessening theseverity of the disorders or diseases as contemplated herein. The exactamount required will vary from subject to subject, depending on thespecies, age, and general condition of the subject, the severity of theinfection, the particular agent, its mode of administration, and thelike. Provided compounds are preferably formulated in unit dosage formfor ease of administration and uniformity of dosage. The expression“unit dosage form” as used herein refers to a physically discrete unitof agent appropriate for the patient to be treated. It will beunderstood, however, that the total daily usage of the compounds andcompositions of the present disclosure will be decided by the attendingphysician within the scope of sound medical judgment. The specificeffective dose level for any particular patient or organism will dependupon a variety of factors including the disorder being treated and theseverity of the disorder; the activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, sex and diet of the patient; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific compound employed, and like factors wellknown in the medical arts.

Pharmaceutically acceptable compositions of this disclosure can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), buccally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, provided compounds may be administered orally orparenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg andpreferably from about 1 mg/kg to about 25 mg/kg, of subject body weightper day, one or more times a day, to obtain the desired therapeuticeffect.

Compounds and compositions described herein are generally useful for theinhibition of activity of one or more proteins involved in epigeneticregulation. Thus, in some embodiments, the present description providesa method of inhibiting one or more proteins involved in epigeneticregulation, such as proteins containing acetyl-lysine recognitionmotifs, also known as bromodomains (e.g., BET proteins, such as BRD2,BRD3, BRD4, and/or BRDT), by administering a provided compound orcomposition.

Examples of proteins inhibited by the compounds and compositionsdescribed herein and against which the methods described herein areuseful include bromodomain-containing proteins, such as BET proteins,such as BRD2, BRD3, BRD4, and/or BRDT, or an isoform or mutant thereof.The activity of a provided compound, or composition thereof, as aninhibitor of a bromodomain-containing protein, such as a BET protein,such as BRD2, BRD3, BRD4, and/or BRDT, or an isoform or mutant thereof,may be assayed in vitro, in vivo, or in a cell line. In vitro assaysinclude assays that determine inhibition of bromodomain-containingproteins, such as BET proteins, such as BRD2, BRD3, BRD4, and/or BRDT,or a mutant thereof. Alternatively, inhibitor binding may be determinedby running a competition experiment where a provided compound isincubated with a bromodomain-containing protein, such as a BET protein,such as BRD2, BRD3, BRD4, and/or BRDT bound to known ligands, labeled orunlabeled. Detailed conditions for assaying a provided compound as aninhibitor of a bromodomain-containing protein, such as a BET protein,such as BRD2, BRD3, BRD4, and/or BRDT or a mutant thereof.

The present description provides for a method of treating a subject witha MYC-dependent cancer, comprising: identifying a subject in need oftreatment; administering to the subject a BET inhibitor; determining atleast one of MYC mRNA expression, MYC protein expression and tumor mass,and wherein following administration, there is a decrease in at leastone of MYC mRNA expression, MYC protein expression and tumor mass,thereby treating the disease.

In one embodiment, the identification step comprises determining whetherthe subject has at least one of a MYC translocation, a geneticrearrangement of MYC, MYC amplification, MYC over-expression and atleast one cellular function that facilitates cellular and/or tumorgrowth and is altered upon reduction of MYC mRNA or protein expression.

The present description also provides for a method of treating a subjectwith a MYC-dependent cancer, comprising: determining at least one of MYCmRNA expression, MYC protein expression and tumor mass; administering tothe subject a BET inhibitor; and comparing at least one of MYC mRNAexpression, MYC protein expression and tumor mass in the subject beforeand after administration of the BET inhibitor.

The present description also provides a method of treating a subjectwith a MYC-dependent cancer, comprising: administering to the subject aBET inhibitor that is identified as capable of decreasing at least oneof MYC mRNA expression, MYC protein expression and tumor mass; anddetermining at least one of MYC mRNA expression, MYC protein expressionand tumor mass; wherein following the administration, there is adecrease in at least one of MYC mRNA expression, MYC protein expressionand tumor mass, thereby treating the disease.

The present description also provides for a method of treating a subjectwith a disease, comprising: administering a BET inhibitor that isidentified as capable of decreasing at least one of MYC mRNA expression,MYC protein expression and tumor mass, wherein following theadministration, there is a decrease in at least one of MYC mRNAexpression, MYC protein expression and tumor mass, thereby treating thedisease.

Acetylated histone recognition and bromodomain-containing proteins (suchas BET proteins) have been implicated in proliferative disease. BRD4knockout mice die shortly after implantation and are compromised intheir ability to maintain an inner cell mass, and heterozygotes displaypre- and postnatal growth defects associated with reduced proliferationrates. BRD4 regulates genes expressed during M/GI, includinggrowth-associated genes, and remains bound to chromatin throughout thecell cycle (Dey, et al. (2009) Mol. Biol. Cell 20:4899-4909). BRD4 alsophysically associates with Mediator and P-TEFb (CDK9/cyclin TI) tofacilitate transcriptional elongation (Yang, et al. (2005) Oncogene24:1653-1662; Yang, et al. (2005) Mol. Cell 19:535-545). CDK9 is avalidated target in chronic lymphocytic leukemia (CLL), and is linked toc-MYC-dependent transcription (Phelps, et al. Blood 113:2637-2645; Rahl,et al. (2010) Cell 141:432-445).

BRD4 is translocated to the NUT protein in patients with lethal midlinecarcinoma, an aggressive form of human squamous carcinoma (French, etal. (2001) Am. J. Pathol. 159:1987-1992; French, et al. (2003) CancerRes. 63:304-307). In vitro analysis with RNAi supports a causal role forBRD4 in this recurrent t(15;19) chromosomal translocation. Pharmacologicinhibition of the BRD4 bromodomains results in growtharrest/differentiation of BRD4-NUT cell lines in vitro and in vivo(Filippakopoulos, et al. “Selective Inhibition of BET Bromodomains,”Nature (published online Sep. 24, 2010)).

Bromodomain-containing proteins (such as BET proteins) have also beenimplicated in inflammatory diseases. BET proteins {e.g., BRD2, BRD3,BRD4, and BRDT) regulate assembly of histone acetylation-dependentchromatin complexes that control inflammatory gene expression(Hargreaves, et al. (2009) Cell 138:129-145; LeRoy, et al. (2008) Mol.Cell 30:51-60; Jang, et al. (2005) Mol. Cell 19:523-534; Yang, et al.(2005) Mol. Cell 19:535-545). Key inflammatory genes (secondary responsegenes) are down-regulated upon bromodomain inhibition of the BETsubfamily, and non-responsive genes (primary response genes) are poisedfor transcription. BET bromodomain inhibition protects againstLPS-induced endotoxic shock and bacteria-induced sepsis in vivo(Nicodeme, et al. “Suppression of Inflammation by a Synthetic HistoneMimic,” Nature (published online Nov. 10, 2010)).

Bromodomain-containing proteins (such as BET proteins) also play a rolein viral disease. For example, BRD4 is implicated in human papillomavirus (HPV). In the primary phase of HPV infection of basal epithelia,the viral genome is maintained in an extra-chromosomal episome. In somestrains of HPV, BRD4 binding to the HPV E2 protein functions to tetherthe viral genome to chromosomes. E2 is critical for both the repressionof E6/E7 and te activation of HPV viral genes. Disruption of BRD4 or theBRD4-E2 interaction blocks E2-dependent gene activation. BRD4 alsofunctions to tether other classes of viral genomes to host chromatin(e.g., Herpesvirus, Epstein-Barr virus).

In certain embodiments, a provided compound inhibits one or more ofBRD2, BRD3, BRD4, BRDT, and/or another member of thebromodomain-containing proteins, or a mutant thereof. In someembodiments, a provided compound inhibits two or more of BRD2, BRD3,BRD4, BRDT, and/or another member of the bromodomain-containingproteins, or a mutant thereof. Provided compounds are inhibitors of oneof more of the bromodomain-containing proteins, such as BRD2, BRD3,BRD4, and/or BRDT and are therefore useful for treating one or moredisorders associated with activity of one or more of thebromodomain-containing proteins, such as BRD2, BRD3, BRD4, and/or BRDT.Thus, in certain embodiments, the present description provides a methodfor treating an bromodomain-containing protein-mediated disorder, suchas a BET-mediated, a BRD2-mediated, a BRD3-mediated, a BRD4-mediateddisorder, and/or a BRDT-mediated disorder comprising the step ofinhibiting a bromodomain-containing protein, such as a BET protein, suchas BRD2, BRD3, BRD4, and/or BRDT, or a mutant thereof, by administeringto a patient in need thereof a provided compound, or a pharmaceuticallyacceptable composition thereof.

As used herein, the terms “bromodomain-containing protein-mediated”,“BET-mediated”, “BRD2-mediated”, “BRD3-mediated”, “BRD4-mediated”,and/or “BRDT-mediated” disorders or conditions means any disease orother deleterious condition in which one or more of thebromodomain-containing proteins, such as BET proteins, such as BRD2,BRD3, BRD4 and/or BRDT, or a mutant thereof, are known to play a role.

In some embodiments, the BET family bromodomain can be BRD2, BRD3 orBRD4.

Accordingly, another embodiment of the present description relates totreating or lessening the severity of one or more diseases in which oneor more of the bromodomain-containing proteins, such as BET proteins,such as BRD2, BRD3, BRD4, and/or BRDT, or a mutant thereof, are known toplay a role.

Diseases and conditions treatable according to the methods of thepresent description include, but are not limited to, cancer and otherproliferative disorders, inflammatory diseases, sepsis, autoimmunedisease, and viral infection. Thus one aspect is a method of treating asubject having a disease, disorder, or symptom thereof the methodincluding administration of a compound or composition herein to thesubject. In one embodiment, a human patient is treated with a compoundof the present description and a pharmaceutically acceptable carrier,adjuvant, or vehicle, wherein said compound is present in an amount tomeasurably inhibit bromodomain-containing protein activity (such as BETprotein, e.g., BRD2, BRD3, BRD4, and/or BRDT) in the patient.

The present description further relates to the use of provided compoundsfor the production of pharmaceutical compositions which are employed forthe treatment and/or prophylaxis and/or amelioration of the diseases,disorders, illnesses and/or conditions as mentioned herein.

The present description further relates to the use of provided compoundsfor the production of pharmaceutical compositions which are employed forthe treatment and/or prophylaxis of diseases and/or disorders responsiveor sensitive to the inhibition of bromodomain-containing proteins,particularly those diseases mentioned above, such as e.g. cancer,inflammatory disease, viral disease.

According to some embodiments, the present description relates to amethod of inhibiting bromodomain-containing proteins in a biologicalsample comprising the step of contacting said biological sample with aprovided compound, or a composition thereof.

According to some embodiments, the present description relates to amethod of inhibiting a bromodomain-containing protein, such as a BETprotein, such as BRD2, BRD3, BRD4 and/or BRDT, or a mutant thereof,activity in a biological sample comprising the step of contacting saidbiological sample with a provided compound, or a composition thereof.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof, biopsied materialobtained from a mammal or extracts thereof, and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of activity of a protein, e.g., a bromodomain-containingprotein such as a BET protein (e.g. BRD2, BRD3, BRD4 and/or BRDT), or amutant thereof, in a biological sample is useful for a variety ofpurposes that are known to one of skill in the art. Examples of suchpurposes include, but are not limited to, blood transfusion,organ-transplantation, biological specimen storage, and biologicalassays.

According to another embodiment, the present description relates to amethod of inhibiting activity of one or more bromodomain-containingprotein, such as a BET protein, such as BRD2, BRD3, BRD4, and/or BRDT,or a mutant thereof, in a patient comprising the step of administeringto said patient a provided compound, or a composition comprising saidcompound. In certain embodiments, the present description provides amethod for treating a disorder mediated by one or morebromodomain-containing proteins, such as a BET protein, such as BRD2,BRD3, BRD4, and/or BRDT, or a mutant thereof, in a patient in needthereof, comprising the step of administering to said patient a providedcompound or pharmaceutically acceptable composition thereof. Suchdisorders are described in detail herein.

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents that are normally administered to treatthat condition may also be present in the compositions of thisdisclosure or administered separately as a part of a dosage regimen. Asused herein, additional therapeutic agents that are normallyadministered to treat a particular disease, or condition, are known as“appropriate for the disease, or condition, being treated.”

In some embodiments, the composition of a compound or compoundsdescribed herein can be in combination with an additional therapeuticagent.

In some embodiments, the additional therapeutic agent is an epigeneticdrug. As used herein, the term “epigenetic drug” refers to a therapeuticagent that targets an epigenetic regulator. Examples of epigeneticregulators include the histone lysine methyltransferases, histonearginine methyl transferases, histone demethylases, histonedeacetylases, histone acetylases, and DNA methyltransferases. Histonedeacetylase inhibitors include, but are not limited to, vorinostat.

Other therapies, chemotherapeutic agents, or other anti-proliferativeagents may be combined with a provided compound to treat proliferativediseases and cancer. Examples of therapies or anticancer agents that maybe used in combination with compounds herein described include surgery,radiotherapy (e.g., gamma-radiation, neutron beam radiotherapy, electronbeam radiotherapy, proton therapy, brachytherapy, and systemicradioactive isotopes), endocrine therapy, a biologic response modifier(e.g., an interferon, an interleukin, tumor necrosis factor (TNF),hyperthermia and cryotherapy, an agent to attenuate any adverse effects(e.g., an antiemetic), and any other approved chemotherapeutic drug.

A provided compound may also be used to advantage in combination withone or more antiproliferative compounds. Such antiproliferativecompounds include an aromatase inhibitor; an anti-estrogen; ananti-androgen; a gonadorelin agonist; a topoisomerase I inhibitor; atopoisomerase II inhibitor; a microtubule active agent; an alkylatingagent; a retinoid, a carotenoid, or a tocopherol; a cyclooxygenaseinhibitor; an MMP inhibitor; an mTOR inhibitor; an antimetabolite; aplatin compound; a methionine aminopeptidase inhibitor; abisphosphonate; an antiproliferative antibody; a heparanase inhibitor;an inhibitor of Ras oncogenic isoforms; a telomerase inhibitor; aproteasome inhibitor; a compound used in the treatment of hematologicmalignancies; a Flt-3 inhibitor; an Hsp90 inhibitor; a kinesin spindleprotein inhibitor; a MEK inhibitor; an antitumor antibiotic; anitrosourea; a compound targeting/decreasing protein or lipid kinaseactivity, a compound targeting/decreasing protein or lipid phosphataseactivity, or any further anti-angiogenic compound.

Exemplary aromatase inhibitors include steroids, such as atamestane,exemestane and formestane, and non-steroids, such as aminoglutethimide,rogletimide, pyridoglutethimide, trilostane, testolactone, ketoconazole,vorozole, fadrozole, anastrozole and letrozole.

Exemplary anti-estrogens include tamoxifen, fulvestrant, raloxifene andraloxifene hydrochloride. Anti-androgens include, but are not limitedto, bicalutamide. Gonadorelin agonists include, but are not limited to,abarelix, goserelin and goserelin acetate.

Exemplary topoisomerase I inhibitors include topotecan, gimatecan,irinotecan, camptothecin and its analogues, 9-nitrocamptothecin and themacromolecular camptothecin conjugate PNU-166148. Topoisomerase IIinhibitors include, but are not limited to, the anthracyclines such asdoxorubicin, daunorubicin, epirubicin, idarubicin and nemorubicin, theanthraquinones mitoxantrone and losoxantrone, and the podophillotoxinsetoposide and teniposide.

Exemplary microtubule active agents include microtubule stabilizing,microtubule destabilizing compounds and microtubulin polymerizationinhibitors including, but not limited to taxanes, such as paclitaxel anddocetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate,vincristine or vincristine sulfate, and vinorelbine; discodermolides;colchicine and epothilones and derivatives thereof.

Exemplary alkylating agents include cyclophosphamide, ifosfamide,melphalan or nitrosoureas such as carmustine and lomustine.

Exemplary cyclooxygenase inhibitors include Cox-2 inhibitors, 5-alkylsubstituted 2-arylaminophenylacetic acid and derivatives, such ascelecoxib, rofecoxib, etoricoxib, valdecoxib or a5-alkyl-2-arylaminophenylacetic acid, such as lumiracoxib.

Exemplary matrix metalloproteinase inhibitors (“MMP inhibitors”) includecollagen peptidomimetic and non-peptidomimetic inhibitors, tetracyclinederivatives, batimastat, marimastat, prinomastat, metastat, BMS-279251,BAY 12-9566, TAA211, MMI270B, and AAJ996.

Exemplary mTOR inhibitors include compounds that inhibit the mammaliantarget of rapamycin (mTOR) and possess antiproliferative activity suchas sirolimus, everolimus, CCI-779, and ABT578.

Exemplary antimetabolites include 5-fluorouracil (5-FU), capecitabine,gemcitabine, DNA demethylating compounds, such as 5-azacytidine anddecitabine, methotrexate and edatrexate, and folic acid antagonists suchas pemetrexed.

Exemplary platin-containing compounds include carboplatin, cisplatin,nedaplatin, and oxaliplatin.

Exemplary methionine aminopeptidase inhibitors include bengamide or aderivative thereof and PPI-2458.

Exemplary bisphosphonates include etidronic acid, clodronic acid,tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid,risedronic acid and zoledronic acid.

Exemplary antiproliferative antibodies include trastuzumab,trastuzumab-DMI, cetuximab, bevacizumab, rituximab, PR064553, and 2C4.The term “antibody” is meant to include intact monoclonal antibodies,polyclonal antibodies, multispecific antibodies formed from at least twointact antibodies, and antibody fragments, so long as they exhibit thedesired biological activity.

Exemplary heparanase inhibitors include compounds that target, decreaseor inhibit heparin sulfate degradation, such as PI-88 and OGT2115.

The term “an inhibitor of Ras oncogenic isoforms,” such as H-Ras, K-Ras,or N-Ras, as used herein refers to a compound which targets, decreases,or inhibits the oncogenic activity of Ras; for example, a farnesyltransferase inhibitor such as L-744832, DK8G557, tipifarnib, andlonafarnib.

Exemplary telomerase inhibitors include compounds that target, decreaseor inhibit the activity of telomerase, such as compounds which inhibitthe telomerase receptor, such as telomestatin.

Exemplary proteasome inhibitors include compounds that target, decreaseor inhibit the activity of the proteasome including, but not limited to,bortezomib.

The phrase “compounds used in the treatment of hematologic malignancies”as used herein includes FMS-like tyrosine kinase inhibitors, which arecompounds targeting, decreasing or inhibiting the activity of FMS-liketyrosine kinase receptors (Flt-3R); interferon,1-β-D-arabinofuransylcytosine (ara-c) and busulfan; and ALK inhibitors,which are compounds which target, decrease or inhibit anaplasticlymphoma kinase.

Exemplary Flt-3 inhibitors include PKC412, midostaurin, a staurosporinederivative, SU11248 and MLN518.

Exemplary HSP90 inhibitors include compounds targeting, decreasing orinhibiting the intrinsic ATPase activity of HSP90; degrading, targeting,decreasing or inhibiting the HSP90 client proteins via the ubiquitinproteosome pathway. Compounds targeting, decreasing or inhibiting theintrinsic ATPase activity of HSP90 are especially compounds, proteins orantibodies which inhibit the ATPase activity of HSP90, such as17-allylamino, 17-demethoxygeldanamycin (17AAG), a geldanamycinderivative; other geldanamycin related compounds; radicicol and HDACinhibitors.

The phrase “a compound targeting/decreasing a protein or lipid kinaseactivity; or a protein or lipid phosphatase activity; or any furtheranti-angiogenic compound” as used herein includes a protein tyrosinekinase and/or serine and/or threonine kinase inhibitor or lipid kinaseinhibitor, such as a) a compound targeting, decreasing or inhibiting theactivity of the platelet-derived growth factor-receptors (PDGFR), suchas a compound which targets, decreases, or inhibits the activity ofPDGFR, such as an N-phenyl-2-pyrimidine-amine derivatives, such asimatinib, SU101, SU6668 and GFB-111; b) a compound targeting, decreasingor inhibiting the activity of the fibroblast growth factor-receptors(FGFR); c) a compound targeting, decreasing or inhibiting the activityof the insulin-like growth factor receptor I (IGF-IR), such as acompound which targets, decreases, or inhibits the activity of IGF-IR;d) a compound targeting, decreasing or inhibiting the activity of theTrk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) acompound targeting, decreasing or inhibiting the activity of the Axlreceptor tyrosine kinase family; f) a compound targeting, decreasing orinhibiting the activity of the Ret receptor tyrosine kinase; g) acompound targeting, decreasing or inhibiting the activity of theKit/SCFR receptor tyrosine kinase, such as imatinib; h) a compoundtargeting, decreasing or inhibiting the activity of the c-Kit receptortyrosine kinases, such as imatinib; i) a compound targeting, decreasingor inhibiting the activity of members of the c-Abl family, theirgene-fusion products (e.g. Bcr-Abl kinase) and mutants, such as anN-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib;PD180970; AG957; NSC 680410; PD173955; or dasatinib; j) a compoundtargeting, decreasing or inhibiting the activity of members of theprotein kinase C (PKC) and Raf family of serine/threonine kinases,members of the MEK, SRC, JAK, FAK, PDK1, PKB/Akt, and Ras/MAPK familymembers, and/or members of the cyclin-dependent kinase family (CDK),such as a staurosporine derivative disclosed in U.S. Pat. No. 5,093,330,such as midostaurin; examples of further compounds include UCN-01,safingol, BAY 43-9006, bryostatin 1, perifosine; ilmofosine; RO 318220and RO 320432; GO 6976; ISIS 3521; LY333531/LY379196; a isochinolinecompound; a farnesyl transferase inhibitor; PD184352 or QAN697, orAT7519; k) a compound targeting, decreasing or inhibiting the activityof a protein-tyrosine kinase, such as imatinib mesylate or a tyrphostinsuch as Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer;Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin(4-{[(2,5-dihydroxyphenyl)methyl] amino}-benzoic acid adamantyl ester;NSC 680410, adaphostin); 1) a compound targeting, decreasing orinhibiting the activity of the epidermal growth factor family ofreceptor tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 as homo- orheterodimers) and their mutants, such as CP 358774, ZD 1839, ZM 105180;trastuzumab, cetuximab, gefitinib, erlotinib, OSI-774, CI-1033, EKB-569,GW-2016, antibodies EI.I, E2.4, E2.5, E6.2, E6.4, E2I.I, E6.3 andE7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; and m) a compoundtargeting, decreasing or inhibiting the activity of the c-Met receptor.

Exemplary compounds that target, decrease or inhibit the activity of aprotein or lipid phosphatase include inhibitors of phosphatase 1,phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.

Further anti-angiogenic compounds include compounds having anothermechanism for their activity unrelated to protein or lipid kinaseinhibition, e.g. thalidomide and TNP-470.

Additional exemplary chemotherapeutic compounds, one or more of whichmay be used in combination with provided compounds, include:daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone,idarubicin, carboplatinum, PKC412, 6-mercaptopurine (6-MP), fludarabinephosphate, octreotide, SOM230, FTY720, 6-thioguanine, cladribine,6-mercaptopurine, pentostatin, hydroxyurea,2-hydroxy-IH-isoindole-1,3-dionederivatives,l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or apharmaceutically acceptable salt thereof,l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate,angiostatin, endostatin, anthranilic acid amides, ZD4190, ZD6474,SU5416, SU6668, bevacizumab, rhuMAb, rhuFab, macugen; FLT-4 inhibitors,FLT-3 inhibitors, VEGFR-2 IgGI antibody, RPI 4610, bevacizumab, porfimersodium, anecortave, triamcinolone, hydrocortisone, 11α-epihydrocotisol,cortexolone, 17α-hydroxyprogesterone, corticosterone,desoxycorticosterone, testosterone, estrone, dexamethasone,fluocinolone, a plant alkaloid, a hormonal compound and/or antagonist, abiological response modifier, such as a lymphokine or interferon, anantisense oligonucleotide or oligonucleotide derivative, shRNA or siRNA,or a miscellaneous compound or compound with other or unknown mechanismof action.

For a more comprehensive discussion of updated cancer therapies see: TheMerck Manual, 17^(th)Ed. 1999. See also the National Cancer Institute(CNI) website (www.nci.nih.gov) and the Food and Drug Administration(FDA) website for a list of the FDA approved oncology drugs.

Other examples of additional therapeutic agents, one or more of which aprovided compound may also be combined with include: a treatment forAlzheimer's Disease such as donepezil and rivastigmine; a treatment forParkinson's Disease such as L-DOPA/carbidopa, entacapone, ropinirole,pramipexole, bromocriptine, pergolide, trihexyphenidyl, and amantadine;an agent for treating multiple sclerosis (MS) such as beta interferon{e.g., Avonex® and Rebif®), glatiramer acetate, and mitoxantrone; atreatment for asthma such as albuterol and montelukast; an agent fortreating schizophrenia such as zyprexa, risperdal, seroquel, andhaloperidol; an anti-inflammatory agent such as a corticosteroid, a TNFblocker, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; animmunomodulatory agent, including immunosuppressive agents, such ascyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, aninterferon, a corticosteroid, cyclophosphamide, azathioprine, andsulfasalazine; a neurotrophic factor such as an acetylcholinesteraseinhibitor, an MAO inhibitor, an interferon, an anti-convulsant, an ionchannel blocker, riluzole, or an anti-Parkinson's agent; an agent fortreating cardiovascular disease such as a beta-blocker, an ACEinhibitor, a diuretic, a nitrate, a calcium channel blocker, or astatin; an agent for treating liver disease such as a corticosteroid,cholestyramine, an interferon, and an anti-viral agent; an agent fortreating blood disorders such as a corticosteroid, an anti-leukemicagent, or a growth factor; or an agent for treating immunodeficiencydisorders such as gamma globulin.

The above-mentioned compounds, one or more of which can be used incombination with a provided compound, can be prepared and administeredas described in the art.

Provided compounds can be administered alone or in combination with oneor more other therapeutic compounds, possible combination therapy takingthe form of fixed combinations or the administration of a providedcompound and one or more other therapeutic compounds being staggered orgiven independently of one another, or the combined administration offixed combinations and one or more other therapeutic compounds. Providedcompounds can besides or in addition be administered especially fortumor therapy in combination with chemotherapy, radiotherapy,immunotherapy, phototherapy, surgical intervention, or a combination ofthese. Long-term therapy is equally possible as is adjuvant therapy inthe context of other treatment strategies, as described above. Otherpossible treatments are therapy to maintain the patient's status aftertumor regression, or even chemopreventive therapy, for example inpatients at risk.

Such additional agents may be administered separately from a compositioncontaining a provided compound, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a provided compound in a single composition. Ifadministered as part of a multiple dosage regimen, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

Upon improvement of a subject's condition, a maintenance dose of acompound, composition or combination of the present description may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level, treatment should cease. Thesubject may, however, require intermittent treatment on a long-termbasis upon any recurrence of disease symptoms.

It will be understood, however, that the total daily usage of thecompounds and compositions of the present description will be decided bythe attending physician within the scope of sound medical judgment. Thespecific inhibitory dose for any particular patient will depend upon avariety of factors including the disorder being treated and the severityof the disorder; the activity of the specific compound employed; thespecific composition employed; the age, body weight, general health, sexand diet of the patient; the time of administration, route ofadministration, and rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed; and like factors well known in themedical arts.

The total daily inhibitory dose of the compounds of the presentdescription administered to a subject in single or in divided doses canbe in amounts, for example, from 0.01 to 50 mg/kg body weight or moreusually from 0.1 to 25 mg/kg body weight. Single dose compositions maycontain such amounts or submultiples thereof to make up the daily dose.In one embodiment, treatment regimens according to the presentdescription comprise administration to a patient in need of suchtreatment from about 10 mg to about 1000 mg of the compound(s) of thepresent description per day in single or multiple doses.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with the present description. For example, aprovided compound may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form. Accordingly, an embodiment of the presentdescription provides a single unit dosage form comprising a providedcompound, an additional therapeutic agent, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle for use in the methods of thepresent description.

The amount of both, a provided compound and additional therapeutic agent(in those compositions which comprise an additional therapeutic agent asdescribed above) that may be combined with the carrier materials toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. Preferably, compositionsshould be formulated such that a dosage of between 0.01-100 mg/kg bodyweight/day of a provided compound can be administered.

In those compositions which comprise an additional therapeutic agent,that additional therapeutic agent and the provided compound may actsynergistically. Therefore, the amount of additional therapeutic agentin such compositions will be less than that required in a monotherapyutilizing only that therapeutic agent. In such compositions a dosage ofbetween 0.01-1,000 g/kg body weight/day of the additional therapeuticagent can be administered.

The amount of additional therapeutic agent present in the compositionsof this disclosure will be no more than the amount that would normallybe administered in a composition comprising that therapeutic agent asthe only active agent. Preferably the amount of additional therapeuticagent in the presently disclosed compositions will range from about 50%to 100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

Provided compounds, or pharmaceutical compositions thereof, may also beincorporated into compositions for coating an implantable medicaldevice, such as prostheses, artificial valves, vascular grafts, stentsand catheters. Vascular stents, for example, have been used to overcomerestenosis (re-narrowing of the vessel wall after injury). However,patients using stents or other implantable devices risk clot formationor platelet activation. These unwanted effects may be prevented ormitigated by pre-coating the device with a pharmaceutically acceptablecomposition comprising a provided compound. Implantable devices coatedwith a compound of the present description are another embodiment of thepresent description.

In another aspect, the present description provides a method of methodof synthesizing a compound of any of the formulae herein. Anotherembodiment is a method of making a compound of any of the formulaeherein using any one, or combination of, reactions delineated herein.The method can include the use of one or more intermediates or chemicalreagents delineated herein.

The recitation of a listing of chemical groups in any definition of avariable herein includes definitions of that variable as any singlegroup or combination of listed groups. The recitation of an embodimentfor a variable herein includes that embodiment as any single embodimentor in combination with any other embodiments or portions thereof. Therecitation of an embodiment herein includes that embodiment as anysingle embodiment or in combination with any other embodiments orportions thereof.

EXAMPLES

The Examples set forth herein below provide syntheses and experimentalresults obtained for certain exemplary compounds. Unless otherwiseindicated, all numbers expressing quantities of ingredients, reactionconditions, concentrations, properties, stabilities, and so forth usedin the specification and claims are to be understood as being modifiedin all instances by the term “about.” At the very least, each numericalparameter should at least be construed in light of the number ofreported significant digits and by applying ordinary roundingtechniques. Accordingly, unless indicated to the contrary, the numericalparameters set forth in the present specification and attached claimsare approximations that may vary depending upon the properties sought tobe obtained. Notwithstanding that the numerical ranges and parameterssetting forth the broad scope of the embodiments are approximations, thenumerical values set forth in the specific examples are reported asprecisely as possible. Any numerical value, however, inherently containcertain errors resulting from variations in experiments, testingmeasurements, statistical analyses and such.

The following is to be construed as merely illustrative, and notlimitations of the preceding disclosure in any way whatsoever. Thoseskilled in the art will promptly recognize appropriate variations fromthe procedures both as to reactants and as to reaction conditions andtechniques.

In some cases, starting materials or intermediates may be commerciallyavailable. Commercial material may be generally available from knownsources, for example, Sigma-Aldrich, Bachem, Lancaster, Alfa Aesar, etc.

Chemical Synthesis of Exemplary Compounds General:

All temperatures are in degrees Celsius (° C.) and are uncorrected.Reagent grade chemicals and anhydrous solvent were purchased fromcommercial sources and unless otherwise mentioned, were used withoutfurther purification The names of the products were determined using thenaming software included in the Contour Software AB electronic labnotebook iLabber™ version 4.11.3075.18678. Flash chromatography wasperformed on Teledyne Isco instruments using pre-packaged disposableSiO₂ stationary phase columns with eluent flow rate range of 5 to 300mL/min, UV detection (254 and 280 nm). Unless otherwise indicated, HPLCpurifications were performed on a Gilson™ HPLC with a Phenomenex Gemini™column, C18, 150:30 mm, 5 micron, eluting at 40 mL/min with mixtures ofMeOH and water containing 0.1% (NH₄)₂CO₃ (high pH), or mixtures of MeCNand water containing 0.1% formic acid (low pH). Chiral isomerseparations were performed, for instance, on a Minigram Semi-PreparativeSFC™ from Mettler-Toledo. Analytical HPLC chromatograms were performedusing an Agilent 1100 series instrument. The mass spectra were recordedwith a Waters Micromass ZQ™ detector at 120° C. The mass spectrometerwas equipped with an electrospray ion source (ESI) operated in apositive ion mode and was set to scan between m/z 150-750 with a scantime of 0.3 s. Products and intermediates were analyzed by HPLC/MS on aX-Bridge™ C₁₈, (3.5 μM, 2.10×30 mm) using a high pH buffer gradient of5% to 95% of MeOH in H₂O (0.03% (NH₄)₂CO₃/0.375% NH₄OH) over 4.5 min at1 mL/min for a 6 min run. The ¹H NMR spectra were recorded on a BrukerUltraShield™ 500 MHz/54 mm instrument (BZH 43/500/70B, D221/54-3209) oron a Bruker Ultra Shield Avance 400 MHz/5 mm Probe (BBFO). The chemicalshifts are reported in part-per-million from a tetramethylsilanestandard.

As used herein, the following abbreviations may have the followingmeanings:

ABBREVIATION TERM

-   -   AcOH Acetic acid    -   BF₃.Et₂O Boron trifluoride diethyl etherate    -   CDCl₃ Deuterated chloroform    -   CHCl₃ Chloroform    -   m-CPBA 3-chloroperoxybenzoic acid    -   Cs₂CO₃ Cesium carbonate    -   d Day(s)    -   DCE 1,2-dichloroethane    -   DCM Dichloromethane    -   DEA Diethylamine    -   DIPEA N,N-diisopropylethylamine    -   DME 1,2-dimethoxyethane    -   DMF N,N-dimethyl formamide    -   DMSO Dimethylsulfoxide    -   Et₂O Diethyl ether    -   EtOAc Ethyl acetate    -   Et₃SiH Triethylsilane    -   h Hour(s)    -   HATU        (dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminium        hexafluorophosphate    -   HCl Hydrochloric acid    -   HNO₃ Nitric Acid    -   HPLC High-performance liquid chromatography    -   H₂SO₄ Sulfuric Acid    -   IPA Isopropanol    -   K₂CO₃ Potassium carbonate    -   KOH Potassium hydroxide    -   LaCl₃.2LiCl Lanthanum(III) chloride bis(lithium chloride)        complex    -   LC-MS Liquid chromatography mass spectrum    -   LiOH.H₂O Lithium hydroxide monohydrate    -   min Minute(s)    -   MeCN Acetonitrile    -   MeOD Deuterated methanol    -   MeOH Methanol    -   MgSO₄ Magnesium sulfate    -   MS (ESI) Electrospray ionization mass spectrometry    -   N₂ Nitrogen    -   NaBH₄ Sodium borohydride    -   Na₂CO₃ Sodium carbonate    -   NaHCO₃ Sodium bicarbonate    -   Na(OAc)₃BH Sodium triacetoxyborohydride    -   NaOH Sodium hydroxide    -   Na₂SO₄ Sodium sulfate    -   NH₄Cl Ammonium chloride    -   NH₄OH Ammonium hydroxide    -   NMR Nuclear magnetic resonance    -   Pd(PPh₃)₄ Tetrakis(triphenylphosphine)palladium(0)    -   POCl₃ Phosphorus(V) oxychloride    -   rt Room temperature    -   SFC Supercritical fluid chromatography    -   SOCl₂ Thionyl chloride    -   TEA Triethylamine    -   TH F Tetrahydrofuran    -   TFA Trifluoroacetic acid

wherein R⁵ is as herein defined, CH₂R, CH(OH)R, CH(OMe)R and CH₂XR eachrepresents an embodiment of R¹ as herein defined, wherein X is O or NH.

wherein R^(x) is hydrogen or R^(a), R^(y) is R^(a), or R^(x) and R^(y)are taken together to form a heterocycloalkyl or heteroaryl, whereinR^(a) is the same or different in each occurrence and is as definedherein.

wherein R^(x) is hydrogen or R^(a), R^(y) is R^(a), or R^(x) and R^(y)are taken together to form a heterocycloalkyl or heteroaryl, whereinR^(a) is the same or different in each occurrence and is as definedherein.

Intermediate 1: 6-bromo-3-(chloromethyl)imidazo[1,2-a]pyridine

Step 1: Preparation of (6-bromoimidazo[1,2-a]pyridin-3-yl) methanol

To solid NaBH₄ (8 mg, 0.227 mmol) was added water (0.1 mL) and then6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde (100 mg, 0.444 mmol), MeOH(0.7 mL) and DCM (0.7 mL) were added and the reaction mixture wasstirred at rt for 2 h. The mixture was concentrated under reducedpressure and the material was triturated with ether and thenconcentrated under reduced pressure to provide the title compound (74mg, 73%). ¹H NMR (500 MHz, DMSO) δ 8.65 (d, J=1.1 Hz, 1H), 7.57 (d,J=9.1 Hz, 1H), 7.53 (s, 1H), 7.38 (dd, J=9.5, 1.9 Hz, 1H), 5.29 (bs,1H), 4.80 (s, 2H). MS (ESI) [M+H]⁺ 227.0/229.0.

Step 2: Preparation of 6-bromo-3-(chloromethyl)imidazo[1,2-a]pyridine

To (6-bromoimidazo[1,2-a]pyridin-3-yl)methanol (0.1 g, 0.44 mmol) wasadded SOCl₂ (1 mL) and the mixture was heated to 60° C. for 2 h. Thesolution was cooled and then concentrated under reduced pressure toafford Intermediate 1 (140 mg), which was used in the next step withoutany further purification. ¹H NMR (500 MHz, DMSO) δ 9.33-9.15 (m, 1H),8.32 (s, 1H), 8.11 (dd, J=9.5, 1.7 Hz, 1H), 7.98 (dd, J=9.5, 0.8 Hz,1H), 5.39 (s, 2H). MS (ESI) [M+H]⁺ 241.1, 243.1.

Intermediate 2:6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxylicacid

Step 1: Preparation of ethyl6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxylate

A stirred solution of ethyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate(1 g, 3.71 mmol) and1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one(prepared as in US20130053362, 1.11 g, 4.46 mmol) in 1,4-dioxane (20 mL)was purged with N₂ for 10 min followed by addition of a solution ofNa₂CO₃ (1.2 g, 11.15 mmol) in water (4.2 mL) and was again purged withN₂ for 10 min. After 10 min, Pd(PPh₃)₄ (0.22 g, 0.19 mmol) was added andthe reaction mixture was heated at 100° C. for 3 h. The solvent wasevaporated under vacuum, water (100 mL) was added and the aqueous layerwas extracted with EtOAc (3×50 mL). The combined organic layers werewashed with brine (100 mL), dried over Na₂SO₄, filtered and evaporatedunder reduced pressure. The material was purified by flashchromatography on silica gel using a mixture of 2% methanol in DCM aseluent to afford the title compound (1 g, 86%) as a solid. ¹H NMR (400MHz, DMSO) δ ppm 9.31 (s, 1H), 8.29 (s, 1H), 8.09 (d, J=2.4 Hz, 1H),7.88 (d, J=9.2 Hz, 1H), 7.80 (dd, J=2 and 1.6 Hz, 1H), 7.70 (d, J=1.2Hz, 1H), 4.37 (q, J=7.2 Hz, 2H), 3.54 (s, 3H), 2.10 (s, 3H), 1.36 (t,3H). MS (ESI) [M+H]⁺ 312.3.

Step 2: Preparation of6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxylicacid

To a stirred solution of ethyl6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxylate(1 g, 3.21 mmol) in THF (20 mL) and water (20 mL) was added LiOH.H₂O(0.15 g, 3.53 mmol) at rt and the reaction mixture was stirred for 3 h.The mixture was acidified with diluted HCl (pH=2) and the resultingsolid was filtered, washed with water (50 mL) and dried under vacuum toafford Intermediate 2 (0.8 g, 88%) as a solid. ¹H NMR (400 MHz, DMSO) δppm 13.39 (bs, 1H), 9.34 (s, 1H), 8.27 (s, 1H), 8.06 (d, J=2.4 Hz, 1H),7.85 (d, J=9.2 Hz, 1H), 7.74 (dd, J=2.0 and 1.6 Hz, 1H), 7.68 (d, J=1.2Hz, 1H), 3.54 (s, 3H), 2.11 (s, 3H). MS (ESI) [M+H]⁺ 284.3.

Intermediate 3: 6-bromoimidazo[1,2-a]pyridine-3-sulfonyl chloride

Step 1: Preparation of 6-bromoimidazo[1,2-a]pyridine-3-sulfonic acid

To a stirred solution of 6-bromoimidazo[1,2-a]pyridine (1 g, 5.08 mmol)in chloroform (15 mL), a solution of chlorosulfonic acid (1 mL, 15.23mmol) in chloroform (10 mL) was added and the reaction mixture wasrefluxed for 16 h. The mixture was concentrated under vacuum, thematerial was treated with a mixture of diethyl ether and ethanol (2:1,30 mL), and the resulting solid was filtered to afford the titlecompound (1.2 g, 85%). ¹H NMR (400 MHz, DMSO) δ ppm 8.92 (t, J=1 Hz,1H), 8.28 (s, 1H), 8.10 (dd, J=1.6 and 9.6 Hz, 1H), 7.37 (dd, J₁, J₂=0.4Hz, 1H). MS (ESI) [M+H]⁺ 279.5.

Step 2: Preparation of 6-bromoimidazo[1,2-a]pyridine-3-sulfonyl chloride

To 6-bromoimidazo[1,2-a]pyridine-3-sulfonic acid (1.2 g, 4.33 mmol) wasadded POCOl₃ (12 mL, 128.53 mmol) and the reaction mixture was heated atreflux temperature for 16 h. The solution was evaporated under reducedpressure, the residue was diluted with water (50 mL) and the aqueouslayer was extracted with DCM (3×50 mL). The organic layers werecombined, dried over Na₂SO₄, filtered and evaporated under reducedpressure to afford Intermediate 3 (0.8 g, 62%) as a solid, which wasused in the next step without purification. MS (ESI) [M+H]⁺ 297.4.

Intermediate 4:5-(3-aminoimidazo[1,2-a]pyridin-6-yl)-1,3-dimethyl-pyridin-2-one

Step 1: Preparation of 6-bromo-3-nitro-imidazo[1,2-a]pyridine

To a solution of 6-bromoimidazo[1,2-a]pyridine (100 mg, 0.508 mmol) inconcentrated H₂SO₄ (0.4 mL) was added at rt concentrated HNO₃ (0.12 mL,2.69 mmol) and the reaction mixture was stirred for 15 min. The mixturewas quenched by the addition of ice and the resulting solid (123 mg,99%) was collected by filtration and used directly in the next stepwithout further purification. ¹H NMR (500 MHz, DMSO) δ 9.40 (t, J=1.4Hz, 1H), 8.78 (s, 1H), 8.00-7.85 (m, 2H). MS (ESI) [M+H]⁺ 242.1/244.1.

Step 2: Preparation of1,3-dimethyl-5-(3-nitroimidazo[1,2-a]pyridin-6-yl)pyridin-2-one

To a suspension of 6-bromo-3-nitro-imidazo[1,2-a]pyridine (535 mg, 2.21mmol) in DME (5 mL) was added1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(prepared using the procedure described in US20130053362, 661 mg, 2.65mmol), Cs₂CO₃ (1.8 g, 5.53 mmol), Pd(PPh₃)₄ (256 mg, 0.22 mmol) andwater (1 mL). The reaction mixture was degassed with N₂ and then heatedin a sealed tube at 90° C. for 18 h. The mixture was cooled to rt andthe resulting solid was collected by filtration, washed with water anddried under vacuum to afford the title compound (472 mg, 75%), which wasused directly in the next step without further purification. ¹H NMR (500MHz, DMSO) δ 9.39 (s, 1H), 8.78 (s, 1H), 8.17 (d, J=2.5 Hz, 1H),8.06-7.98 (m, 2H), 7.78 (d, J=1.4 Hz, 1H), 3.55 (s, 3H), 2.11 (s, 3H).MS (ESI) [M+H]⁺ 285.2.

Step 3: Preparation of5-(3-aminoimidazo[1,2-a]pyridin-6-yl)-1,3-dimethyl-pyridin-2-one

To a suspension of1,3-dimethyl-5-(3-nitroimidazo[1,2-a]pyridin-6-yl)pyridin-2-one (160 mg,0.56 mmol) in MeOH (10 mL) was added AcOH (0.10 mL, 1.69 mmol) and zinc(368 mg, 5.63 mmol) and the resulting suspension mixture was stirred atrt for 1 h. The mixture was filtered through a pad of Celite™, washedwith MeOH and then the filtrate was concentrated under reduced pressure.The residue was triturated with a DCM/MeOH mixture to affordIntermediate 4 (91 mg, 64%) as a solid. MS (ESI) [M+H]⁺ 255.2.

Example 1:5-(3-benzylimidazo[1,2-a]pyridin-6-yl)-1,3-dimethyl-pyridin-2-one(Compound 1)

Step 1: Preparation of(6-bromoimidazo[1,2-a]pyridin-3-yl)-phenyl-methanol

To a solution of phenyl magnesium bromide (3 M in THF, 0.40 mL, 1.21mmol) in dry THF (0.5 mL) was added a solution of6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde (210 mg, 0.933 mmol) in THF(5 mL) at −30° C. More phenyl magnesium bromide (0.4 mL, 1.21 mmol) wasadded and the mixture was stirred for 30 min at −30° C. The mixture wasthen quenched with water and concentrated under reduced pressure. EtOAc(50 mL) and saturated NH₄Cl (10 mL) were added and the phases wereseparated. The aqueous phase was then extracted with EtOAc (3×30 mL).The combined organic layers were washed with brine, filtered, dried andevaporated under reduced pressure to provide the title compound, whichwas used in the next step without any further purification (230 mg,81%). MS (ESI) [M+H]⁺ 303.1/305.1.

Step 2: Preparation of 3-benzyl-6-bromo-imidazo[1,2-a]pyridine

TFA (3.78 mL, 49.3 mmol) was cooled to 0° C. and sodium borohydride (168mg, 4.55 mmol) was added in portion. The mixture was stirred until nomore solid was observed (about 20-30 min). The mixture was then added toa solution of (6-bromoimidazo[1,2-a]pyridin-3-yl)-phenyl-methanol (230mg, 0.759 mmol) in DCM (16 mL) and the mixture was stirred for 5 hours.The reaction was quenched with saturated NaHCO₃ (added until thereaction became basic) and EtOAc (30 mL) was added. Phases wereseparated and aqueous phase was extracted with EtOAc (2×20 mL). Thecombined organic phases were washed with brine, dried and concentratedunder reduced pressure. The material was purified by flashchromatography on silica gel using a mixture of EtOAc in hexane aseluent to provide the title compound (0.17 g), which was used in thenext step without further purification. MS (ESI) [M+H]⁺ 287.1/289.1.

Step 3: Preparation of Compound 1

3-benzyl-6-bromo-imidazo[1,2-a]pyridine (80 mg, 0.279 mmol),3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(prepared using the procedure described in US20130053362, 83 mg, 0.334mmol) in a solution of DME (2 mL) and water (0.1 mL) was degassed bybubbling N₂ for 10 min. Pd(PPh₃)₄ (32 mg, 0.028 mmol) and Cs₂CO₃ (191mg, 0.585 mmol) were added. The resulting mixture was heated to 85° C.for 4 h and then cooled to rt. The mixture was concentrated underreduced pressure and then diluted with saturated NaHCO₃ (10 mL) andEtOAc (10 mL), and the aqueous phase was extracted with EtOAc (3×10 mL).The combined organic phases were dried over MgSO₄, filtered, andconcentrated under reduced pressure. The material was purified by flashchromatography on silica gel using a mixture of EtOAc on hexane followedby 10% MeOH in DCM and then by preparative HPLC to provide Compound 1(15 mg, 16%). ¹H NMR (500 MHz, CDCl₃) δ 7.75 (s, 1H), 7.68 (d, J=9.4 Hz,1H), 7.52 (s, 1H), 7.39-7.33 (m, 2H), 7.30 (dd, J=6.7, 4.2 Hz, 2H),7.27-7.17 (m, 4H), 4.32 (s, 2H), 3.62 (s, 3H), 2.21 (s, 3H). MS (ESI)[M+H]⁺ 330.3.

Example 2:5-[3-[(4-fluorophenyl)methyl]imidazo[1,2-a]pyridin-6-yl]-1,3-dimethyl-pyridin-2-one(Compound 2)

Step 1: Preparation of(6-bromoimidazo[1,2-a]pyridin-3-yl)-(4-fluorophenyl)methanol

To a suspension of magnesium (148 mg, 6.18 mmol) in THF (1 mL) was added1-bromo-4-fluorobenzene (0.25 mL, 2.27 mmol) and the mixture was heatedto 50° C. for a few seconds. The mixture was then stirred for 5 min andthen the rest of 1-bromo-4-fluorobenzene (0.25 mL, 2.27 mmol) was added.The stirring was continued for 15 min and then the mixture was heated to50° C. for about 30 min until most of the solid magnesium disappeared.The mixture was then allowed to cool to rt and 1 mL of this mixture wasthen treated with a solution of6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde (160 mg, 0.711 mmol) in THF(5 mL) at −30° C. and the mixture was stirred for 30 min. The reactionwas then quenched by addition of a saturated solution of NH₄Cl (5 mL)and then diluted in EtOAc (30 mL). The layers were separated and theaqueous layer was extracted with EtOAc (2×20 mL). The combined organiclayers were washed with brine, dried and concentrated under reducedpressure. The material was purified by flash chromatography on silicagel using a mixture of EtOAc in hexane as eluent to provide the titlecompound (61%). MS (ESI) [M+H]⁺ 321.1/323.1.

Step 2: Preparation of6-bromo-3-[(4-fluorophenyl)methyl]imidazo[1,2-a]pyridine

TFA (2.17 mL, 28.34 mmol) was cooled to 0° C. and sodium borohydride (97mg, 2.62 mmol) was added in one portion. The mixture was stirred untilno more solid observed (about 30 min). Half of this mixture was thenadded to a solution of(6-bromoimidazo[1,2-a]pyridin-3-yl)-phenyl-methanol (140 mg, 0.436 mmol)in DCM (16 mL) and the mixture was stirred for 4 h. Half of the firstmixture of TFA/NaBH₄ (kept at 0° C.) was then added to the reaction andthe mixture stirred for 2 more hours. The reaction was quenched withsaturated NaHCO₃ (5 mL) and EtOAc (30 mL) was added. Phases wereseparated and aqueous phase was extracted with EtOAc (2×20 mL). Thecombined organic phases were washed with brine, dried and concentratedunder reduced pressure. The material was purified by flashchromatography on silica gel using a mixture of EtOAc in hexane toprovide the title compound (37 mg, 28%). MS (ESI) [M+H]⁺ 305.1/307.1.

Step 3: Preparation of Compound 2

A mixture of1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(prepared using the procedure described in US20130053362, 36 mg, 0.146mmol), 6-bromo-3-[(4-fluorophenyl)methyl]imidazo[1,2-a]pyridine (37 mg,0.121 mmol) in DME (2 mL) and water (0.1 mL) was degassed by bubbling N₂for 10 min. Cs₂CO₃ (83 mg, 0.255 mmol) and Pd(PPh₃)₄ (14 mg, 0.012 mmol)were then added and the mixture was degassed for 10 more min. Theresulting mixture was heated to 85° C. for 3 h and then cooled to rt.The mixture was diluted with saturated NaHCO₃ (10 mL) and EtOAc (10 mL),and the aqueous phase was extracted with EtOAc (3×10 mL). The combinedorganic phases were dried over MgSO₄, filtered, and concentrated underreduced pressure. The material product was purified by flashchromatography on silica gel using a mixture of EtOAc in hexane aseluent, and followed by preparative HPLC to provide Compound 2 (11 mg,24%). ¹H NMR (500 MHz, MeOD) δ 8.32 (s, 1H), 7.86 (d, J=2.5 Hz, 1H),7.71-7.59 (m, 3H), 7.40 (s, 1H), 7.36-7.28 (m, 2H), 7.12-7.02 (m, 2H),4.37 (s, 2H), 3.65 (s, 3H), 2.18 (s, 3H). MS (ESI) [M+H]⁺ 348.2.

Example 3:5-[3-[(4-chlorophenyl)methyl]imidazo[1,2-a]pyridin-6-yl]-1,3-dimethyl-pyridin-2-one(Compound 3)

Step 1: Preparation of(6-bromoimidazo[1,2-a]pyridin-3-yl)-(4-chlorophenyl) methanol

To a solution of 4-chlorophenylmagnesium bromide (1M in THF, 1.2 mL, 1.2mmol) in dry THF (1.5 mL) was added6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde (140 mg, 0.62 mmol) at −30°C. and the reaction mixture was stirred for 60 min at −30° C. More4-chlorophenylmagnesium bromide (1M in THF, 1.2 mL, 1.2 mmol) was thenadded and the mixture was stirred for 2 h. To the mixture, was addedsaturated NH₄Cl and the solution was concentrated under reducedpressure. To the residue, EtOAc (50 mL) and saturated NaHCO₃ (10 mL)were added and phases were separated. The aqueous phase was thenextracted with EtOAc (3×30 mL). The combined organic phases were washedwith brine, dried over Na₂SO₄, filtered and then evaporated underreduced pressure. The material was purified over by flash chromatographyon silica gel using a mixture of EtOAc in hexane as eluent to providethe title compound (130 mg, 62%). MS (ESI) [M+H]⁺ 339.0.

Step 2: Preparation of6-bromo-3-[(4-chlorophenyl)methyl]imidazo[1,2-a]pyridine

TFA (3.78 mL, 49.29 mmol) was cooled to 0° C. and sodium borohydride(171 mg, 4.62 mmol) was added in portion. The mixture was stirred untilno more solid was observed (about 30 min). The mixture was then added toa solution of(6-bromoimidazo[1,2-a]pyridin-3-yl)-(4-chlorophenyl)methanol (130 mg,0.385 mmol) in DCM (2 mL) and the reaction mixture was stirred for 4 hat rt. To the mixture, saturated NaHCO₃ (5 mL) and EtOAc (30 mL) wereadded. The phases were separated and the aqueous phase was extractedwith EtOAc (2×20 mL). The combined organic phases were washed withbrine, dried over Na₂SO₄, filtered and then concentrated under reducedpressure. The material was purified by flash chromatography on silicagel using a mixture of EtOAc in hexane as eluent to provide the titlecompound (50 mg, 40%). MS (ESI) [M+H]⁺ 323.0.

Step 3: Preparation of Compound 3

A mixture of1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(prepared using the procedure described in US20130053362, 50 mg, 0.202mmol), 6-bromo-3-[(4-chlorophenyl)methyl]imidazo[1,2-a]pyridine (50 mg,0.155 mmol) in DME (2 mL) and water (0.1 mL) was degassed by bubbling N₂for 10 min. Cs₂CO₃ (106 mg, 0.326 mmol) and Pd(PPh₃)₄ (18 mg, 0.016mmol) were then added and the mixture was degassed for 10 more min andthe resulting mixture was heated to 85° C. for 4 h. The mixture wascooled to rt and then concentrated under reduced pressure. The mixturewas diluted with saturated NaHCO₃ (10 mL) and EtOAc (10 mL), and theaqueous layer was extracted with EtOAc (3×10 mL). The combined organiclayers were dried over MgSO₄, filtered, and concentrated under reducedpressure. The material was purified by flash chromatography using amixture of EtOAc in hexane as eluent, followed by preparative HPLC toprovide Compound 3 (11 mg, 17%). ¹H NMR (500 MHz, MeOD) δ 8.29 (s, 1H),7.85 (d, J=2.5 Hz, 1H), 7.71-7.64 (m, 2H), 7.61 (dd, J=9.4, 1.7 Hz, 1H),7.41 (s, 1H), 7.37-7.31 (m, 2H), 7.29 (d, J=8.6 Hz, 2H), 4.38 (s, 2H),3.65 (s, 3H), 2.19 (s, 3H). MS (ESI) [M+H]⁺ 364.2.

Example 4:5-[3-[(4-methoxyphenyl)methyl]imidazo[1,2-a]pyridin-6-yl]-1,3-dimethyl-pyridin-2-one(Compound 4)

Step 1: Preparation of(6-bromoimidazo[1,2-a]pyridin-3-yl)-(4-methoxyphenyl)methanol

To a solution of 4-methoxyphenylmagnesium bromide (1M in THF, 2 mL, 1mmol) in dry THF (1.5 mL) was added a solution of6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde (150 mg, 0.667 mmol) in THF(5 mL) at −30° C. and the reaction mixture was stirred 60 min at −30° C.Saturated NH₄Cl was added to the mixture and the solution wasconcentrated under reduced pressure. To the residue, EtOAc (50 mL) andsaturated NaHCO₃ (10 mL) were added. The layers were separated and theaqueous layer was extracted with EtOAc (3×30 mL). The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andevaporated under reduced pressure. The material was purified by flashchromatography on silica gel using a mixture of EtOAc in hexane toprovide the title compound (120 mg, 54%). MS (ESI) [M+H]⁺ 333.0/335.0.

Step 2: Preparation of6-bromo-3-[(4-methoxyphenyl)methyl]imidazo[1,2-a]pyridine

(6-Bromoimidazo[1,2-a]pyridin-3-yl)-(4-methoxyphenyl)methanol (40 mg,0.12 mmol) was suspended in DCM (1.5 mL), BF₃*Et₂O (52 mL, 0.42 mmol)and Et₃SiH (0.06 mL, 0.3 mmol) were added dropwise, and the reactionmixture was stirred for 10 min. To the mixture, saturated NaHCO₃ (5 mL)was added, followed by DCM (30 mL). The aqueous layer was extracted withDCM (2×20 mL). The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure to afford the titlecompound (40 mg), which was used in the next step without any furtherpurification. MS (ESI) [M+H]⁺ 317.1/319.1.

Step 3: Preparation of Compound 4

A solution of 6-bromo-3-[(4-methoxyphenyl)methyl]imidazo[1,2-a]pyridine(40 mg, 0.126 mmol),1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(prepared using the procedure described in US20130053362, 40 mg, 0.164mmol) in DME (2 mL) and water (0.1 mL) was degassed by bubbling N₂ for10 min. Cs₂CO₃ (86 mg, 0.265 mmol) and Pd(PPh₃)₄ (15 mg, 0.013 mmol)were then added and the mixture was degassed for another 10 min. Theresulting mixture was heated to 85° C. overnight and then allowed tocool to rt. To the mixture, saturated NaHCO₃ (10 mL) and EtOAc (10 mL)were added, and the aqueous layer was extracted with EtOAc (3×10 mL).The combined organic layers were dried over MgSO₄, filtered, andevaporated under reduced pressure. The product was purified by flashchromatography on silica gel using a mixture of EtOAc in hexane aseluent, followed by preparative HPLC to provide Compound 4 (11 mg, 24%).¹H NMR (500 MHz, MeOD) δ 8.26 (d, J=32.2 Hz, 1H), 7.83 (d, J=1.6 Hz,1H), 7.74-7.58 (m, 3H), 7.41 (s, 1H), 7.21 (d, J=8.4 Hz, 2H), 6.89 (d,J=8.5 Hz, 2H), 4.30 (s, 2H), 3.74 (s, 3H), 3.63 (s, 3H), 2.18 (s, 3H).MS (ESI) [M+H]⁺ 360.2.

Example 5:5-[3-[(3-fluorophenyl)methyl]imidazo[1,2-a]pyridin-6-yl]-1,3-dimethyl-pyridin-2-one(Compound 5)

Step 1: Preparation of(6-bromoimidazo[1,2-a]pyridin-3-yl)-(3-fluorophenyl)methanol

1-Fluoro-3-iodo-benzene (554 mg, 2.49 mmol) was added dropwise toisopropylmagnesium chloride (1M solution, 0.995 mL, 0.995 mmol) at rt.After 15 min, the Grignard was ready to use. LaCl₃.2LiCl (0.6 M in THF,1.66 mL, 0.995 mmol) was added to a solution of6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde (224 mg, 0.995 mmol) in THF(4 mL) at rt. The mixture was stirred for 30 min at rt, then the aboveGrignard solution was added dropwise at rt and the reaction mixture wasstirred for 1 h. To the mixture, saturated NH₄Cl (5 mL) was added andthe solution was concentrated under reduced pressure. To the residue,EtOAc (30 mL) and saturated NaHCO₃ (10 mL) were added. The phases wereseparated and the aqueous layer was extracted with EtOAc (2×50 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The material waspurified by flash chromatography on silica gel to provide the titlecompound (0.32 g, 31%). ¹H NMR (500 MHz, CDCl₃) δ 8.38 (d, J=1.1 Hz,1H), 7.47 (d, J=9.5 Hz, 1H), 7.42-7.33 (m, 1H), 7.28-7.25 (m, 1H),7.24-7.19 (m, 2H), 7.18-7.15 (m, 1H), 7.12-7.00 (m, 1H), 6.17 (s, 1H),3.12-2.80 (m, 1H). MS (ESI) [M+H]321.0, 323.0.

Step 2: Preparation of6-bromo-3-[(3-fluorophenyl)methyl]imidazo[1,2-a]pyridine

(6-bromoimidazo[1,2-a]pyridin-3-yl)-(3-fluorophenyl)methanol (40 mg,0.125 mmol) was suspended in DCM (1.5 mL) and BF₃*Et₂O (0.054 mL, 0.436mmol) and Et₃SiH (0.058 mL, 0.311 mmol) were added dropwise. Thereaction mixture was stirred for 1 h and then saturated NaHCO₃ (5 mL)was added, followed by DCM (30 mL). The aqueous phase was then extractedwith DCM (2×20 mL). The combined organic layers were dried over Na₂SO₄,filtered and evaporated under reduced pressure to afford the titlecompound (39 mg), which was used in the next step without furtherpurification. MS (ESI) [M+H]⁺ 305.1, 307.1.

Step 3: Preparation of Compound 5

A solution of 6-bromo-3-[(3-fluorophenyl)methyl]imidazo[1,2-a]pyridine(39 mg, 0.128 mmol),1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(prepared using the procedure described in US20130053362, 41 mg, 0.166mmol) in DME (2 mL) and water (0.1 mL) was degassed by bubbling N₂ for10 min. Cs₂CO₃ (87 mg, 0.268 mmol) and Pd(PPh₃)₄ (14 mg, 0.013 mmol)were then added and the mixture was degassed for another 10 min. Theresulting mixture was heated to 85° C. for 3 h and then cooled to rt. Tothe mixture, saturated NaHCO₃ (10 mL) and EtOAc (10 mL) were added, andthe aqueous layer was extracted with EtOAc (3×10 mL). The combinedorganic layers were dried over MgSO₄, filtered, and concentrated underreduced pressure. The material was purified by flash chromatography onsilica gel using a mixture of EtOAc in hexane as eluent, followed bypreparative HPLC to provide Compound 5 (13 mg, 29%). ¹H NMR (500 MHz,CDCl₃) δ 7.75-7.69 (m, 1H), 7.66 (dd, J=9.3, 0.7 Hz, 1H), 7.50 (s, 1H),7.34-7.27 (m, 2H), 7.25-7.17 (m, 2H), 7.02-6.99 (m, 1H), 6.97 (td,J=8.4, 2.5 Hz, 1H), 6.90 (dd, J=9.6, 1.7 Hz, 1H), 4.28 (s, 2H), 3.60 (s,3H), 2.20 (s, 3H). MS (ESI) [M+H]⁺ 348.1.

Examples 6-7:5-[3-[methoxy(phenyl)methyl]imidazo[1,2-a]pyridin-6-yl]-1,3-dimethyl-pyridin-2-oneisomers (Compounds 6 and 7)

Compound 6 (RT: 7.07)—Compound 7 (RT: 9.61) Step 1: Preparation of6-bromo-3-[methoxy(phenyl)methyl]imidazo[1,2-a]pyridine

To a solution of 3-phenylprop-2-ynal (111 mg, 0.85 mmol),5-bromopyridin-2-amine (147.6 mg, 0.853 mmol) in MeOH (3 mL) was addedacetic acid (1 drop) and the reaction mixture was heated to 80° C. for 8h. The mixture was concentrated under reduced pressure and the materialwas purified by flash chromatography on silica using a mixture of EtOAcand hexane as eluent to afford the title compound as a mixture ofenantiomers (191 mg, 71%). ¹H NMR (500 MHz, CDCl₃) δ 8.25 (dd, J=1.9,0.8 Hz, 1H), 7.52 (dd, J=9.5, 0.8 Hz, 1H), 7.40 (d, J=4.4 Hz, 4H), 7.37(dd, J=8.0, 4.1 Hz, 1H), 7.24 (d, J=1.9 Hz, 2H), 5.60 (s, 1H), 3.40 (s,3H).

Step 2: Preparation of Compounds 6 and 7

To a solution of 6-bromo-3-[methoxy(phenyl)methyl]imidazo[1,2-a]pyridine(50 mg, 0.158 mmol) in dioxane (1 mL) was added Cs₂CO₃ (77 mg, 0.236mmol),1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(prepared using the procedure described in US20130053362, 59 mg, 0.24mmol), Pd(PPh₃)₄ (18 mg, 0.016 mmol) and water (0.1 mL). The reactionmixture was degassed by bubbling N₂ for 10 min and the resulting mixturewas then heated at 80° C. for 18 h. The mixture was cooled to rt andEtOAc (5 mL) and water (5 mL) were added. The organic phase was driedover Na₂SO₄, filtered and evaporated under reduced pressure. Thematerial was purified by flash chromatography on silica gel using amixture of EtOAc and hexane as eluent, followed by semi-preparative SFC(AS 10×250 mm, 5 um Isocratic 25% MeOH+0.1% NH₄OH, 10 mL/min 100 Bar) toafford Compound 6 (18.6 mg, 35%) and Compound 7 (23.4 mg, 43%).

Compound 6: Retention Time=7.07; ¹H NMR (500 MHz, CDCl₃) δ 8.04 (s, 1H),7.65 (d, J=9.3 Hz, 1H), 7.49-7.32 (m, 6H), 7.29 (dd, J=2.6, 1.2 Hz, 1H),7.24 (dd, J=9.3, 1.8 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H), 5.70 (s, 1H), 3.61(s, 3H), 3.44 (s, 3H), 2.22 (s, 3H). MS (ESI) [M+H]⁺ 360.2.

Compound 7: Retention Time=9.61; ¹H NMR (500 MHz, CDCl₃) δ 8.04 (s, 1H),7.65 (d, J=9.3 Hz, 1H), 7.49-7.34 (m, 6H), 7.29 (dd, J=2.5, 1.1 Hz, 1H),7.26-7.23 (m, 1H), 7.21 (d, J=2.4 Hz, 1H), 5.70 (s, 1H), 3.61 (s, 3H),3.44 (s, 3H), 2.22 (s, 3H). MS (ESI) [M+H]⁺ 360.1.

Example 8:1,3-dimethyl-5-[3-(1-piperidylmethyl)imidazo[1,2-a]pyridin-6-yl]pyridin-2-one(Compound 8)

Step 1: Preparation of6-bromo-3-(1-piperidylmethyl)imidazo[1,2-a]pyridine

Piperidine (0.053 mL, 0.533 mmol) was added to a stirred solution of6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde (100 mg, 0.444 mmol) in DCM(4 mL). To this mixture was then added acetic acid (0.076 mL, 1.33 mmol)and the mixture was stirred for 45 min. Na(OAc)₃BH (94 mg, 0.444 mmol)was added and the reaction was stirred for 18 h. Another portion ofNa(OAc)₃BH (188 mg, 0.888 mmol) was added and the reaction mixture wasstirred for 3 h. To the mixture, water and saturated NaHCO₃ (10 mL) wereadded followed by DCM (20 mL). The organic layer was separated and theaqueous layer was extracted with DCM (2×20 mL). The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The material was purified by flashchromatography on silica gel using a mixture of EtOAc in hexane aseluent to provide the title compound (45 mg, 34%). MS (ESI) [M+H]+:294.1, 296.1.

Step 2: Preparation of Compound 8

A solution of 6-bromo-3-(1-piperidylmethyl)imidazo[1,2-a]pyridine (45mg, 0.153 mmol) and1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(prepared using the procedure described in US20130053362, 46 mg, 0.184mmol) in DME (2 mL) and water (0.1 mL) was degassed by bubbling N₂ for10 min. Cs₂CO₃ (105 mg, 0.321 mmol) and Pd(PPh₃)₄ (18 mg, 0.015 mmol)were then added and the mixture was degassed for another 10 min. Theresulting mixture was heated to 85° C. for 3 h and then cooled to rt. Tothe mixture, saturated NaHCO₃ (10 mL) and EtOAc (10 mL) were added, andthe aqueous layer was extracted with EtOAc (3×10 mL). The combinedorganic layers were dried over MgSO₄, filtered, and concentrated underreduced pressure. The material was purified by flash chromatography onsilica gel using a mixture of EtOAc in hexane as eluent, followed bypreparative HPLC to provide Compound 8 (11 mg, 21%). ¹H NMR (500 MHz,CDCl₃) δ 8.44 (d, J=0.9 Hz, 1H), 7.62 (dd, J=9.3, 0.8 Hz, 1H), 7.49 (s,1H), 7.45 (dd, J=2.6, 1.2 Hz, 1H), 7.38 (d, J=2.4 Hz, 1H), 7.23 (dd,J=9.3, 1.9 Hz, 1H), 3.78 (s, 2H), 3.65 (s, 3H), 2.50-2.30 (bs, 3H), 2.25(s, 3H), 1.86 (s, 1H), 1.62-1.48 (m, 4H), 1.50-1.36 (m, 2H). MS (ESI)[M+H]⁺ 337.3.

Example 9:5-[3-(cyclopentoxymethyl)imidazo[1,2-a]pyridin-6-yl]-1,3-dimethyl-pyridin-2-one(Compound 9)

Step 1: Preparation of6-bromo-3-(cyclopentoxymethyl)imidazo[1,2-a]pyridine

To a solution of cyclopentanol (0.074 mL, 0.815 mmol) and DIPEA (0.212mL, 1.22 mmol) in THF (1 mL), Intermediate 1 (100 mg, 0.407 mmol) wasadded and the reaction mixture was heated to 55° C. for 18 h. Themixture was then cooled and concentrated under reduced pressure. To theresidue, EtOAc (30 mL) was added and the organic layer was washed withsaturated NaHCO₃ (7 mL). The aqueous layer was then extracted with EtOAc(2×20 mL). The combined organic layers were washed with brine, driedover MgSO₄, filtered and concentrated under reduced pressure. Thematerial was purified by flash chromatography on silica gel using amixture of EtOAc in hexane as eluent to provide the title compound (40mg, 33%). MS (ESI) [M+H]⁺ 295.0, 297.0.

Step 2: Preparation of Compound 9

A solution of 6-bromo-3-(cyclopentoxymethyl)imidazo[1,2-a]pyridine (40mg, 0.136 mmol) and1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(prepared using the procedure described in US20130053362, 40 mg, 0.163mmol) in DME (2 mL) and water (0.1 mL) was degassed by bubbling N₂ for10 min. Cs₂CO₃ (93 mg, 0.285 mmol) and Pd(PPh₃)₄ (16 mg, 0.014 mmol)were then added and the mixture was degassed for another 10 min. Theresulting mixture was heated to 85° C. for 3 h and then cooled to rt. Tothe mixture, saturated NaHCO₃ (10 mL) and EtOAc (20 mL) were added. Thelayers were separated and the aqueous layer was extracted with EtOAc(3×10 mL). The combined organic layers were dried over MgSO₄, filtered,and concentrated under reduced pressure. The product was purified byflash chromatography on silica gel using a mixture of EtOAc in hexane aseluent, followed by preparative HPLC to provide Compound 9 (7 mg, 13%).¹H NMR (500 MHz, CDCl₃) δ 8.22 (s, 1H), 7.66 (d, J=9.0 Hz, 1H), 7.61 (s,1H), 7.47-7.42 (m, 1H), 7.38 (d, J=2.5 Hz, 1H), 7.28 (dd, J=9.2, 1.7 Hz,1H), 4.82 (s, 2H), 4.09-3.89 (m, 1H), 3.65 (s, 3H), 2.25 (s, 3H),1.86-1.62 (m, 6H), 1.61-1.52 (m, 2H). MS (ESI) [M+H]⁺ 338.3.

Example 10:5-[3-(anilinomethyl)imidazo[1,2-a]pyridin-6-yl]-1,3-dimethyl-pyridin-2-one(Compound 10)

Step 1: Preparation ofN-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methyl]aniline

To a solution of Intermediate 1 (54 mg, 0.22 mmol) in MeCN (2 mL) wasadded aniline (0.024 mL, 0.264 mmol) and K₂CO₃ (85 mg, 0.66 mmol) andthe reaction mixture was heated at 60° C. for 1 h. The mixture wascooled and then concentrated under reduced pressure. To the residue,EtOAc (30 mL) and saturated NaHCO₃ (10 mL) were added. The layers wereseparated and the aqueous layer was extracted with EtOAc (2×20 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and then concentrated under reduced pressure. The material waspurified by flash chromatography on silica gel using a mixture of EtOAcin hexane and then MeOH in EtOAc as eluent to provide the title compound(10 mg, 15%). MS (ESI) [M+H]⁺ 302.1, 304.1.

Step 2: Preparation of Compound 10

A solution of N-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methyl]aniline (10mg, 0.033 mmol) and1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(prepared using the procedure described in US20130053362, 10.7 mg, 0.043mmol) in DME (2 mL) and water (0.1 mL) was degassed by bubbling N₂ for10 min. Cs₂CO₃ (23 mg, 0.069 mmol) and Pd(PPh₃)₄ (4 mg, 0.003 mmol) werethen added and the mixture was degassed for another 10 min. Theresulting mixture was heated to 85° C. for 2 h and then cooled to rt. Tothe mixture, saturated NaHCO₃ (10 mL) and EtOAc (30 mL) were added. Thelayers were separated and the aqueous layer was extracted with EtOAc(3×10 mL). The combined organic layers were dried over MgSO₄, filtered,and concentrated under reduced pressure. The material was purified byflash chromatography on silica gel using a mixture of EtOAc in hexane aseluent, followed by preparative HPLC to provide Compound 10 (5 mg, 44%).¹H NMR (500 MHz, CDCl₃) δ 8.10 (s, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.65 (s,1H), 7.36 (d, J=1.3 Hz, 1H), 7.32-7.25 (m, 4H), 6.84 (t, J=7.4 Hz, 1H),6.78 (d, J=7.7 Hz, 2H), 4.65 (s, 2H), 3.75 (s, 1H), 3.61 (s, 3H), 2.21(s, 3H). MS (ESI) [M+H]⁺ 345.2.

Example 11:1,3-dimethyl-5-(3-(morpholine-4-carbonyl)imidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (Compound 11)

To a stirred solution of Intermediate 2 (0.1 g, 0.35 mmol) in DMF (2 mL)was added HATU (0.2 g, 0.53 mmol) at rt. The mixture was stirred at thistemperature for 30 min, and a solution of morpholine (34 mg, 0.39 mmol)and DIPEA (0.2 mL, 1.05 mmol) in DMF (1 mL) was then added dropwise andthe reaction mixture was stirred at rt for 16 h. The mixture was pouredinto water (30 ml) and the aqueous layer was extracted with EtOAc (3×20mL). The combined organic layers were washed with brine (30 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure. Thematerial was purified by flash chromatography on silica gel using amixture of 3% MeOH in DCM as eluent to afford Compound 11 (15 mg, 12%)as a solid. ¹H NMR (400 MHz, DMSO) δ ppm 9.00 (s, 1H), 8.06 (d, J=2.4Hz, 1H), 8.04 (s, 1H), 7.79 (d, J=9.6 Hz, 1H), 7.70 (s, 1H), 7.68 (d,J=2 Hz, 1H), 3.76-3.75 (m, 4H), 3.69-3.68 (m, 4H), 3.53 (s, 3H), 2.10(s, 3H). MS (ESI) [M+H]⁺ 353.6.

Example 12:N-cyclohexyl-6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide(Compound 12)

To a stirred solution of Intermediate 2 (0.1 g, 0.35 mmol) in DMF (2 mL)was added HATU (0.2 g, 0.53 mmol) at rt. The mixture was stirred at thistemperature for 30 min, a solution of cyclohexanamine (39 mg, 0.39 mmol)and DIPEA (0.2 mL, 1.05 mmol) in DMF (1 mL) was then added dropwise andthe reaction mixture was stirred at rt for 16 h. The reaction mixturewas poured into water (30 mL) and the resulting solid was filtered anddried under reduced pressure. The material was purified by flashchromatography on silica gel using a mixture of 3% MeOH in DCM as eluentto afford Compound 12 (70 mg, 54%) as a solid. ¹H NMR (400 MHz, DMSO) bppm 9.62 (s, 1H), 8.37 (s, 1H), 8.28 (d, J=8 Hz, 1H), 8.05 (d, J=2.4 Hz,1H), 7.76 (dd, J=0.8 and 9.2 Hz, 1H), 7.69 (d, J=2 Hz, 1H), 7.68-7.66(m, 1H), 3.82 (bs, 1H), 3.54 (s, 3H), 2.11 (s, 3H), 1.88-1.86 (m, 2H),1.77-1.76 (m, 2H), 1.64 (d, J=11.6 Hz, 1H), 1.38-1.29 (m, 4H), 1.17-1.16(m, 1H). MS (ESI) [M+H]⁺ 365.6.

Example 13:1,3-dimethyl-5-(3-(piperidine-1-carbonyl)imidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one(Compound 13)

To a stirred solution of Intermediate 2 (0.1 g, 0.35 mmol) in DMF (2 mL)was added HATU (0.2 g, 0.53 mmol) at rt. The mixture was stirred at thattemperature for 30 min, a solution of piperidine (33 mg, 0.39 mmol) andDIPEA (0.2 mL, 1.05 mmol) in DMF (1 mL) was then added dropwise and thereaction mixture was stirred at rt for 16 h. The mixture was poured intowater (30 mL) and the aqueous layer was extracted with EtOAc (3×20 mL).The combined organic layers were washed with brine (30 mL), dried overNa₂SO₄, filtered and evaporated under reduced pressure. The material waspurified by flash chromatography on silica gel using a mixture of 3%MeOH in DCM as eluent to afford Compound 13 (70 mg, 57%) as a solid. ¹HNMR (400 MHz, DMSO) δ ppm 8.95 (s, 1H), 8.05 (s, 1H), 7.96 (s, 1H), 7.76(d, J=9.6 Hz, 1H), 7.70 (s, 1H), 7.66 (d, J=9.2 Hz, 1H), 3.70 (s, 4H),3.53 (s, 3H), 2.10 (s, 3H), 1.67-1.62 (m, 6H). MS (ESI) [M+H]⁺ 351.6.

Example 14:1,3-dimethyl-5-(3-(piperidin-1-ylsulfonyl)imidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one(Compound 14)

Step 1: Preparation of6-bromo-3-(piperidin-1-ylsulfonyl)imidazo[1,2-a]pyridine

To a solution of piperidine (0.086 g, 1.02 mmol) in DCM (2 mL) was addedTEA (0.28 mL, 2.03 mmol) at rt. The mixture was stirred for 5 min, asolution of Intermediate 3 (0.2 g, 0.68 mmol) in DCM (2 mL) was addedand the reaction mixture stirred at rt for 2 h. The mixture was dilutedwith DCM (30 mL) and then washed with water (30 mL) and brine (30 mL).The organic layer was dried over Na₂SO₄, filtered and evaporated underreduced pressure to afford the title compound (0.15 g, 64%). ¹H NMR (400MHz, DMSO) δ ppm 8.80 (q, J=0.8 Hz, 1H), 8.19 (s, 1H), 7.83 (dd, J=0.8and 9.6 Hz, 1H), 7.72 (dd, J=2 and 9.6 Hz, 1H), 3.08 (t, J=5.2 Hz, 4H),1.56-1.50 (m, 4H), 1.42-1.39 (m, 2H). MS (ESI) [M+H]⁺ 346.2.

Step 2: Preparation of Compound 14

A stirred solution of6-bromo-3-(piperidin-1-ylsulfonyl)imidazo[1,2-a]pyridine (0.15 g, 0.44mmol) and1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one(prepared using the procedure described in US20130053362, 0.13 g, 0.52mmol) in 1,4-dioxane (3 mL) was purged with N₂ for 10 min followed bythe addition of a solution of Na₂CO₃ (0.14 g, 1.31 mmol) in water (1mL), which was again purged with N₂ for another 10 min. After 10 min,Pd(PPh₃)₄ (25 mg, 0.022 mmol) was added and the resulting mixture washeated at 100° C. for 3 h. The mixture was concentrated under reducedpressure, water was added and the aqueous layer was extracted with EtOAc(3×20 mL). The combined organic layers were washed with water (20 mL)and brine (20 mL), dried over Na₂SO₄, filtered and evaporated underreduced pressure. The material was purified by flash chromatography onsilica gel using a mixture of 2% methanol in DCM as eluent to affordCompound 14 (0.11 g, 65%) as a solid. ¹H NMR (400 MHz, DMSO) δ ppm 8.74(s, 1H), 8.17 (s, 1H), 8.04 (d, J=2.4 Hz, 1H), 7.91 (d, J=9.6 Hz, 1H),7.80 (dd, J=1.6 and 1.2 Hz, 1H), 7.67 (s, 1H), 3.54 (s, 3H), 3.09 (t,J=5 Hz, 4H), 2.11 (s, 3H), 1.53 (s, 4H), 1.38 (d, J=4.4 Hz, 2H). MS(ESI) [M+H]⁺ 387.5.

Example 15:6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-N-ethylimidazo[1,2-a]pyridine-3-sulfonamide(Compound 15)

Step 1: Preparation of6-bromo-N-ethylimidazo[1,2-a]pyridine-3-sulfonamide

To a solution of ethyl amine (34 mg, 0.76 mmol) in DCM (2 mL) was addedTEA (0.2 mL, 1.52 mmol). The mixture was stirred for 5 min, a solutionof Intermediate 3 (0.15 g, 0.51 mmol) in DCM (1 mL) was added and thereaction mixture was stirred at rt for 2 h. The mixture was diluted withDCM (25 mL), washed with water (25 mL) and brine (25 mL). The organiclayer was dried over Na₂SO₄, filtered and evaporated under vacuum toafford the title compound (0.1 g, 65%), which was used in the next stepwithout purification. MS (ESI) [M+H]⁺ 306.5.

Step 2: Preparation of Compound 15

A stirred solution of6-bromo-N-ethylimidazo[1,2-a]pyridine-3-sulfonamide (0.1 g, 0.33 mmol)and1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one(prepared using the procedure described in US20130053362, 0.122 g, 0.49mmol) in 1,4-dioxane (2 mL) was purged with N₂ for 10 min followed bythe addition of a solution of Na₂CO₃ (0.104 g, 0.99 mmol) in water (0.5mL), which was again purged with N₂ for 10 min. After 10 min, Pd(PPh₃)₄(19 mg, 0.016 mmol) was added and the reaction mixture was heated at100° C. for 3 h. The mixture was diluted with water and the aqueouslayer was extracted using EtOAc (3×20 mL). The combined organic layerswere washed with water (20 mL) and brine (20 mL), dried over Na₂SO₄,filtered and evaporated under reduced pressure. The material waspurified by flash chromatography on silica gel using a mixture of 2-3%methanol in DCM as eluent to afford Compound 15 (17 mg, 15%) as a solid.¹H NMR (400 MHz, DMSO) δ ppm 8.66 (s, 1H), 8.33 (bs, 1H), 8.10 (d, J=2.4Hz, 1H), 8.09 (s, 1H), 7.90 (d, J=9.2 Hz, 1H), 7.79 (dd, J=2.0 and 1.6Hz, 1H), 7.77 (d, J=2.0 Hz, 1H), 3.55 (s, 3H), 2.83 (q, J=8.8 Hz, 2H),2.13 (s, 3H), 0.89 (t, J=7.2 Hz, 3H). MS (ESI) [M+H]⁺ 347.5.

Example 16:N-cyclopentyl-6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide(Compound 16)

Step 1: Preparation of6-bromo-N-cyclopentylimidazo[1,2-a]pyridine-3-sulfonamide

TEA (0.28 mL, 2.03 mmol) was added to a rt stirred solution ofcyclopentylamine (86 mg, 1.02 mmol) in DCM (2 mL). The mixture wasstirred for 5 min, a solution of Intermediate 3 (0.2 g, 0.68 mmol) inDCM (2 mL) was added and the reaction mixture was stirred at rt foranother 2 h. The mixture was diluted with DCM (30 mL) and washed withwater (30 mL) and brine (30 mL). The organic layer was dried overNa₂SO₄, filtered and evaporated under reduced pressure to afford thetitle compound (0.15 g, 64%) as a solid. ¹H NMR (400 MHz, DMSO) δ ppm8.88 (q, J=0.8 Hz, 1H), 8.11 (s, 1H), 7.83 (dd, J=0.8 Hz, 1H), 7.72 (dd,J=1.6 Hz, 1H), 3.46-3.39 (m, 1H), 1.54-1.49 (m, 4H), 1.40-1.34 (m, 2H),1.30-1.21 (m, 2H), —NH was not visible MS. (ESI) [M+H]346.4.

Step 2: Preparation of Compound 16

A stirred solution of6-bromo-N-cyclopentylimidazo[1,2-a]pyridine-3-sulfonamide (0.15 g, 0.44mmol) and1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one(prepared using the procedure described in US20130053362, 0.13 g, 0.52mmol) in 1,4-dioxane (3 mL) was purged with N₂ for 10 min followed bythe addition of a solution of Na₂CO₃ (0.14 g, 1.31 mmol) in water (1mL), which was again purged with nitrogen for another 10 min. After 10min, Pd(PPh₃)₄ (25 mg, 0.022 mmol) was added and the resulting mixturewas heated at 100° C. for 3 h. The mixture was diluted with water andthe aqueous layer was extracted using EtOAc (3×20 mL). The combinedorganic layers were washed with water (20 mL) and brine (20 mL), driedover Na₂SO₄, filtered and then evaporated under reduced pressure. Thematerial was purified by flash chromatography on silica gel using amixture of 2% MeOH in DCM as eluent to afford Compound 16 (0.11 g, 65%)as a solid. ¹H NMR (400 MHz, DMSO) δ ppm 8.67 (s, 1H), 8.44 (d, J=7.2Hz, 1H), 8.10 (d, J=2.8 Hz, 1H), 8.09 (s, 1H), 7.90 (d, J=9.6 Hz, 1H),7.82 (dd, J=1.6 and 9.6 Hz 1H), 7.77 (s, 1H), 3.55 (s, 3H), 3.44-3.39(m, 1H), 2.13 (s, 3H), 1.49 (s, 4H), 1.39-1.33 (m, 2H), 1.19-1.16 (m,2H). MS (ESI) [M+H]⁺ 387.5.

Example 17:6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-N-isopropylimidazo[1,2-a]pyridine-3-sulfonamide(Compound 17)

Step 1: Preparation of6-bromo-N-isopropylimidazo[1,2-a]pyridine-3-sulfonamide

To a rt solution of isopropyl amine (0.045 g, 0.76 mmol) in DCM (2 mL)was added TEA (0.2 mL, 1.52 mmol). The mixture was stirred for 5 min andthen a solution of Intermediate 3 (0.15 g, 0.51 mmol) in DCM (1 mL) wasadded. The reaction mixture was stirred at rt for another 2 h. Themixture was then diluted with DCM (25 mL) and washed with water (25 mL)and brine (25 mL). The organic layer was dried over Na₂SO₄, filtered andevaporated under reduced pressure to afford the title compound (0.1 g,62%), which was used in next step without purification. MS (ESI) [M+H]⁺320.5.

Step 2: Preparation of Compound 17

A stirred solution of6-bromo-N-isopropylimidazo[1,2-a]pyridine-3-sulfonamide (0.1 g, 0.31mmol) and1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one(prepared using the procedure described in US20130053362, 0.117 g, 0.47mmol) in 1,4-dioxane (2 mL) was purged with N₂ for 10 min, followed bythe addition of a solution of Na₂CO₃ (0.1 g, 0.93 mmol) in water (0.5mL). The mixture was then purged again with N₂ for another 10 min. After10 min, Pd(PPh₃)₄ (18 mg, 0.02 mmol) was added and the resulting mixturewas heated at 100° C. for 3 h. The mixture was diluted with water andthe aqueous layer was extracted using ethyl acetate (3×20 mL). Thecombined organic layers were washed with water (20 mL) and brine (20mL), dried over Na₂SO₄ and then evaporated under reduced pressure. Thematerial was purified by flash chromatography on silica gel using amixture of 2-3% MeOH in DCM as eluent to afford Compound 17 (16 mg, 14%)as a solid. ¹H NMR (400 MHz, DMSO) δ ppm 8.66 (s, 1H), 8.41 (d, J=7.6Hz, 1H), 8.10 (d, J=2.8 Hz, 1H), 8.09 (s, 1H), 7.90 (d, J=9.6 Hz, 1H),7.82 (dd, J=2.0 and 9.6 Hz, 1H), 7.78 (d, J=1.2 Hz, 1H), 3.55 (s, 3H),3.27-3.22 (m, 1H), 2.13 (s, 3H), 0.88 (d, J=6.8 Hz, 6H). MS (ESI) [M+H]⁺361.5.

Example 18:N-cyclohexyl-6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide(Compound 18)

Step 1: Preparation of6-bromo-N-cyclohexylimidazo[1,2-a]pyridine-3-sulfonamide

To a solution of cyclohexylamine (38 mg, 0.37 mmol) in DCM (1 mL) wasadded TEA (0.1 mL, 0.75 mmol) at rt. The mixture was stirred for 5 minand then a solution of Intermediate 3 (0.075 g, 0.25 mmol) in DCM (1 mL)was added. The reaction mixture was stirred at rt for another 2 h. Themixture was then diluted with DCM (15 mL) and washed with water (15 mL)and brine (15 mL). The organic layer was dried over Na₂SO₄, filtered andevaporated under reduced pressure to afford the title compound (40 mg,44%), which was used in the next step without purification. MS (ESI)[M+H]⁺ 360.4.

Step 2: Preparation of Compound 18

A stirred solution of6-bromo-N-cyclohexylimidazo[1,2-a]pyridine-3-sulfonamide (40 mg, 0.11mmol) and1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one(prepared using the procedure described in US20130053362, 0.033 g, 0.13mmol) in 1,4-dioxane (1 mL) was purged with N₂ for 10 min. This wasfollowed by the addition of a solution of Na₂CO₃ (43 mg, 0.33 mmol) inwater (0.5 mL), and the reaction mixture was again purged with N₂ for 10min. After 10 min, Pd(PPh₃)₄ (8 mg g, 0.006 mmol) was added and theresulting mixture was heated at 100° C. for 3 h. The mixture was dilutedwith water and the aqueous layer was extracted using EtOAc (3×10 mL).The combined organic layers were washed with water (10 mL) and brine (10mL), dried over Na₂SO₄, filtered and then evaporated under reducedpressure. The material was purified by flash chromatography on silicagel using a mixture of 2-3% MeOH in DCM as eluent to afford Example 18(20 mg, 44%) as a solid. ¹H NMR (400 MHz, DMSO) δ ppm 8.67 (s, 1H), 8.45(d, J=7.6 Hz, 1H), 8.09 (d, J=2.4 Hz, 1H), 8.08 (s, 1H), 7.89 (d, J=9.6Hz, 1H), 7.82 (dd, J=1.6 and 9.2 Hz, 1H), 7.78 (s, 1H), 3.55 (s, 3H),2.96-2.93 (m, 1H), 2.13 (s, 3H), 1.54-1.52 (m, 2H), 1.41-1.39 (m, 3H),1.11-1.01 (m, 5H). MS (ESI) [M+H]⁺ 401.4.

Example 19:1,3-dimethyl-5-(3-(pyrrolidin-1-ylsulfonyl)imidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one(Compound 19)

Step 1: Preparation of6-bromo-3-(pyrrolidin-1-ylsulfonyl)imidazo[1,2-a]pyridine

To a rt solution of pyrrolidine (72 mg, 1.02 mmol) in DCM (2 mL) wasadded TEA (0.28 mL, 2.03 mmol). The mixture was stirred for 5 min andthen a solution of Intermediate 3 (0.2 g, 0.68 mmol) in DCM (2 mL) wasadded. The resulting mixture was stirred at rt for another 2 h. Themixture was diluted with DCM (30 mL) and washed with water (30 mL) andbrine (30 mL). The organic layer was dried over Na₂SO₄, filtered andevaporated under reduced pressure to afford the title compound (0.15 g,67%) as a solid. ¹H NMR (400 MHz, DMSO) δ ppm 8.88 (s, 1H), 8.23 (s,1H), 7.83 (d, J=9.2 Hz, 1H), 7.72 (dd, J=1.6 and 9.6 Hz, 1H), 3.24 (t,J=6.6 Hz, 4H), 1.74 (t, J=6.6 Hz, 4H). MS (ESI) [M+H]⁺ 332.4.

Step 2: Preparation of Compound 19

A stirred solution of6-bromo-3-(pyrrolidin-1-ylsulfonyl)imidazo[1,2-a]pyridine (0.15 g, 0.45mmol) and1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one(prepared using the procedure described in US20130053362, 0.136 g, 0.54mmol) in 1,4-dioxane (3 mL) was purged with N₂ for 10 min. A solution ofNa₂CO₃ (0.145 g, 1.36 mmol) in water (1 mL) was added and the resultingmixture was purged with N₂ for another 10 min. After 10 min, Pd(PPh₃)₄(26 mg, 0.02 mmol) was added and the mixture was heated at 100° C. for 3h. The solvent was evaporated under vacuum and the aqueous layer wasextracted using EtOAc (3×20 mL). The combined organic layers were washedwith water (20 mL) and brine (20 mL), dried over Na₂SO₄, filtered andthen evaporated under reduced pressure. The material was purified byflash chromatography on silica gel using a mixture of 2% MeOH in DCM aseluent to afford Compound 19 (0.11 g, 41%) as a solid. ¹H NMR (400 MHz,DMSO) b ppm 8.80 (s, 1H), 8.21 (s, 1H), 8.04 (d, J=2.4 Hz, 1H), 7.90 (d,J=9.6 Hz, 1H), 7.79 (dd, J=1.6 and 2 Hz, 1H), 7.65 (d, J=1.6 Hz, 1H),3.54 (s, 3H), 3.25 (t, J=6.8 Hz, 4H), 2.11 (s, 3H), 1.75-1.71 (m, 4H).MS (ESI) [M+H]⁺ 373.5.

Example 20:5-[3-[(4,4-difluoro-1-piperidyl)methyl]imidazo[1,2-a]pyridin-6-yl]-1,3-dimethyl-pyridin-2-one(Compound 20)

Step 1: Preparation of6-bromo-3-[(4,4-difluoro-1-piperidyl)methyl]imidazo[1,2-a]pyridine

To a solution of Intermediate 1 (75 mg, 0.31 mmol) in DMF (5 mL) wasadded 4,4-difluoropiperidine hydrochloride (72 mg, 0.46 mmol) and DIPEA(0.19 mL, 1.07 mmol). The reaction mixture was stirred at rt for 18 h.The resulting mixture was diluted with EtOAc (10 mL) and water (10 mL)and the organic layer was separated, dried over MgSO₄, filtered andconcentrated under reduced pressure. The material was purified by flashchromatography on silica gel using a mixture of MeOH in DCM as eluent toafford the title compound (46 mg, 46%) as a solid. MS (ESI) [M+H]⁺330.1/332.1.

Step 2: Preparation of Compound 20

To a solution of6-bromo-3-[(4,4-difluoro-1-piperidyl)methyl]imidazo[1,2-a]pyridine (46mg, 0.14 mmol) in DME (5 mL) and water (0.5 mL) was added1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(prepared using the procedure described in US20130053362, 65 mg, 0.167mmol), Cs₂CO₃ (113.5 mg, 0.35 mmol) and Pd(PPh₃)₄ (16 mg, 0.014 mmol).The resulting mixture was degassed for 5 min with N₂ and then heated ina sealed tube at 90° C. for 18 h. The mixture was cooled to rt, dilutedwith EtOAc (10 mL) and water (5 mL). The organic layer was separated,dried over MgSO₄, filtered and concentrated under reduced pressure. Thematerial was purified by flash chromatography on silica gel using amixture of MeOH in DCM as eluent, followed by preparative HPLCpurification to afford Compound 20 (14.6 mg, 28%) as a solid. ¹H NMR(500 MHz, CDCl₃) δ 8.27 (s, 1H), 7.66 (d, J=9.1 Hz, 1H), 7.55 (s, 1H),7.43 (dd, J=2.5, 1.1 Hz, 1H), 7.36 (d, J=2.4 Hz, 1H), 7.32-7.24 (m, 2H),3.89 (s, 1H), 3.66 (s, 3H), 2.60 (d, J=5.4 Hz, 4H), 2.26 (s, 3H),2.05-1.89 (m, 4H). MS (ESI) [M+H]⁺ 373.1.

Example 21:1,3-dimethyl-5-[3-(morpholinomethyl)imidazo[1,2-a]pyridin-6-yl]pyridin-2-one(Compound 21)

Step 1: Preparation of4-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methyl]morpholine

To a solution of Intermediate 1 (75 mg, 0.305 mmol) in DMF (3 mL) wasadded morpholine (67 L, 0.76 mmol) and the reaction mixture was stirredat rt for 18 h. The mixture was diluted with EtOAc (10 mL) and water (10mL). The organic layer was separated, dried over MgSO₄, filtered andconcentrated under reduced pressure. The material was purified by flashchromatography on silica gel using a mixture of EtOAc and hexane aseluent to afford the title compound (40 mg, 44%) as a solid.

Step 2: Preparation of Compound 21

To a suspension of4-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methyl]morpholine (40 mg, 0.16mmol) in DME (3 mL) was added1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(prepared using the procedure described in US20130053362, 40 mg, 0.16mmol), Cs₂CO₃ (110 mg, 0.34 mmol) and Pd(PPh₃)₄ (16 mg, 0.014 mmol). Thereaction mixture was degassed for 5 min and then heated in a sealed tubeat 90° C. for 18 h. The mixture was cooled to rt and diluted with EtOAc(10 mL) and water (10 mL). The organic layer was separated, dried overMgSO₄, filtered and concentrated under reduced pressure. The materialwas purified by flash chromatography on silica gel using a mixture ofMeOH in DCM as eluent, followed by preparative HPLC purification toafford Compound 21 (10.6 mg, 23%) as a solid. ¹H NMR (500 MHz, CDCl₃) δ8.34 (s, 1H), 7.64 (d, J=9.2 Hz, 1H), 7.53 (s, 1H), 7.44 (dd, J=2.5, 1.2Hz, 1H), 7.36 (d, J=2.4 Hz, 1H), 7.28-7.21 (m, 1H), 3.84 (s, 2H),3.71-3.66 (m, 4H), 3.65 (s, 3H), 2.47 (d, J=4.3 Hz, 4H), 2.25 (s, 3H).MS (ESI) [M+H]⁺ 339.3.

Example 22:5-[3-(cyclopentylamino)imidazo[1,2-a]pyridin-6-yl]-1,3-dimethyl-pyridin-2-one(Compound 22)

Cyclopentanone (0.13 mL, 1.4 mmol) was added to a solution ofIntermediate 4 (178 mg, 0.7 mmol) in DCM (5 mL) and the resultingmixture was stirred at rt for 18 h. The solution was evaporated underreduced pressure. The residue was dissolved in MeOH (5 mL) and thenNaBH₄ (79 mg, 2.1 mmol) was added and the reaction mixture was stirredat rt for another 1 h. The mixture was concentrated and the residue wasdiluted in EtOAc (10 mL) and water (10 mL). The organic layer wasseparated, dried over MgSO₄, filtered and concentrated under reducedpressure. The material was purified by preparative HPLC to affordCompound 22 (4 mg, 2%) as a solid. ¹H NMR (500 MHz, CDCl₃) δ 7.97 (s,1H), 7.57 (d, J=9.4 Hz, 1H), 7.47 (s, 1H), 7.42 (s, 1H), 7.20-7.15 (m,2H), 3.76 (s, 1H), 3.66 (d, J=8.0 Hz, 3H), 2.25 (s, 3H), 2.02-1.93 (m,2H), 1.80 (s, 2H), 1.66-1.48 (m, 5H). MS (ESI) [M+H]⁺ 323.3.

Example 23:5-[3-(cyclopentylmethylamino)imidazo[1,2-a]pyridin-6-yl]-1,3-dimethyl-pyridin-2-one(Compound 23)

To a solution of Intermediate 4 (300 mg, 1.18 mmol) in DCM (5 mL) wasadded cyclopentane carbaldehyde (231 mg, 2.36 mmol) and the mixture wasstirred at rt for 18 h. The solution was concentrated under reducedpressure and the residue was dissolved in MeOH (5 mL). NaBH₄ (134 mg,3.54 mmol) was added and the reaction mixture was stirred at rt for 1 h.The mixture was concentrated and the residue was diluted in EtOAc (10mL) and water (10 mL). The organic layer was separated, dried overMgSO₄, filtered and concentrated under reduced pressure. The materialwas purified by preparative HPLC to afford Compound 23 (12 mg, 3%) as asolid. ¹H NMR (500 MHz, CDCl₃) δ 7.91 (dd, J=1.7, 0.9 Hz, 1H), 7.58-7.52(m, 1H), 7.47 (dd, J=2.5, 1.2 Hz, 1H), 7.39 (d, J=2.5 Hz, 1H), 7.18 (s,1H), 7.12 (dd, J=9.3, 1.8 Hz, 1H), 3.64 (s, 3H), 3.09 (d, J=6.5 Hz, 2H),2.24 (d, J=8.0 Hz, 3H), 2.23-2.16 (m, 1H), 1.93-1.81 (m, 2H), 1.66 (dt,J=8.9, 7.7 Hz, 3H), 1.63-1.56 (m, 2H), 1.38-1.24 (m, 2H). MS (ESI)[M+H]⁺ 337.4.

Example 24:5-(3-benzyl-2-methyl-imidazo[1,2-a]pyridin-6-yl)-1,3-dimethyl-pyridin-2-one(Compound 24)

Step 1: Preparation of5-(3-benzoyl-2-methyl-imidazo[1,2-a]pyridin-6-yl)-1,3-dimethyl-pyridin-2-one

To a solution of(6-bromo-2-methyl-imidazo[1,2-a]pyridin-3-yl)-phenyl-methanone (preparedusing the procedure described in WO2015086498, 279 mg, 0.88 mmol) in DME(3 mL) and water (0.3 mL) was added1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(prepared using the procedure described in US20130053362, 264 mg, 1.06mmol), Cs₂CO₃ (721 mg, 2.21 mmol) and Pd(PPh₃)₄ (102 mg, 0.089 mmol).The reaction mixture was degassed for 5 min and then heated in a sealedtube at 80° C. for 18 h. The mixture was cooled to rt, diluted withEtOAc (10 mL) and water (10 mL). The organic layer was separated, driedover MgSO₄, filtered and concentrated under reduced pressure. Thematerial was purified by flash chromatography on silica gel using amixture of MeOH in DCM as eluent to afford the title compound (200 mg,63%) as a solid. ¹H NMR (500 MHz, CDCl₃) δ 9.47 (dd, J=1.8, 0.8 Hz, 1H),8.07 (d, J=2.5 Hz, 1H), 7.81 (ddd, J=10.0, 9.3, 1.3 Hz, 2H), 7.74-7.61(m, 4H), 7.57 (t, J=7.5 Hz, 2H), 3.53 (s, 3H), 2.10 (s, 3H), 2.04 (s,3H). MS (ESI) [M+H]⁺ 358.2.

Step 2: Preparation of Compound 24

A solution of5-(3-benzoyl-2-methyl-imidazo[1,2-a]pyridin-6-yl)-1,3-dimethyl-pyridin-2-one(50 mg, 0.14 mmol), hydrazine hydrate (0.40 mL, 4.57 mmol) and KOH (63mg, 1.12 mmol) in ethylene glycol (1 mL) was heated in a sealed vial at150° C. for 20 h. The mixture was then cooled to rt and diluted with DCM(10 mL) and H₂O (10 mL). The aqueous layer was separated and extractedwith DCM (3×10 mL). The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure. The material waspurified by preparative HPLC to provide Compound 24 (13 mg, 27%) as asolid. ¹H NMR (500 MHz, CDCl₃) δ 7.61 (dd, J=1.7, 0.9 Hz, 1H), 7.56 (dd,J=9.2, 0.9 Hz, 1H), 7.34-7.22 (m, 4H), 7.14 (ddd, J=6.8, 5.7, 3.1 Hz,4H), 4.29 (s, 2H), 3.58 (s, 3H), 2.52 (s, 3H), 2.19 (s, 3H). MS (ESI)[M+H]⁺ 344.2.

Example 25:5-[3-(cyclobutoxymethyl)imidazo[1,2-a]pyridin-6-yl]-1,3-dimethyl-pyridin-2-one(Compound 25)

Step 1: Preparation of6-bromo-3-(cyclobutoxymethyl)imidazo[1,2-a]pyridine

Intermediate 1 (100 mg, 0.41 mmol) was added to a solution ofcyclobutanol (64 μL, 0.815 mmol) and DIPEA (0.212 mL, 1.22 mmol) in THF(1 mL) and the reaction mixture was heated at 55° C. for 3 d. Themixture was cooled and then diluted with EtOAc (30 mL) and saturatedNaHCO₃ (20 mL). The aqueous layer was separated and extracted with EtOAc(3×20 mL). The combined organic layers were washed with brine, driedover Na₂SO₄, filtered and then concentrated under reduced pressure. Thematerial was purified by flash chromatography on silica gel using amixture of EtOAc in hexane as eluent to provide the title compound (22mg, 19%). ¹H NMR (500 MHz, CDCl₃) δ 8.33 (dd, J=1.8, 0.8 Hz, 1H), 7.55(s, 1H), 7.50 (dt, J=9.2, 2.6 Hz, 1H), 7.30-7.25 (m, 1H), 4.69 (s, 2H),4.00-3.90 (m, 1H), 2.21-2.10 (m, 2H), 1.97-1.85 (m, 2H), 1.76-1.65 (m,1H), 1.57-1.42 (m, 1H). MS (ESI) [M+H]⁺ 281.2.

Step 2: Preparation of Compound 25

Pd(PPh₃)₄ (9 mg, 0.008 mmol) was added to a degassed solution of6-bromo-3-(cyclobutoxymethyl)imidazo[1,2-a]pyridine (22 mg, 0.078 mmol),1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(prepared using the procedure described in US20130053362, 25 mg, 0.102mmol), and Cs₂CO₃ (64 mg, 0.196 mmol) in DME (3 mL) and water (0.3 mL)under N₂. The resulting mixture was heated at 80° C. for 20 h and thencooled to rt. The mixture was filtered through a pad of Celite™ andwashed with EtOAc (100 mL). The organic layer was washed with saturatedNaHCO₃ (100 mL) and the aqueous layer was re-extracted with EtOAc (3×50mL). The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The material was purified by flashchromatography on silica gel using a mixture of EtOAc in hexane aseluent, followed by preparative HPLC to provide Compound 25 (3.8 mg,15%) as a solid. ¹H NMR (500 MHz, CDCl₃) δ 8.20 (s, 1H), 7.66 (d, J=9.4Hz, 1H), 7.59 (s, 1H), 7.46 (s, 1H), 7.39 (d, J=2.4 Hz, 1H), 7.29 (dd,J=9.4, 1.6 Hz, 1H), 4.78 (s, 2H), 4.01 (s, 1H), 3.65 (s, 3H), 2.25 (s,3H), 2.19-2.09 (m, 2H), 1.90 (qd, J=10.0, 2.7 Hz, 2H), 1.72-1.67 (m,1H), 1.49 (dq, J=10.7, 8.1 Hz, 1H). MS (ESI) [M+H]⁺ 324.2.

Example 26:1,3-dimethyl-5-[3-[(2-oxo-1-piperidyl)methyl]imidazo[1,2-a]pyridin-6-yl]pyridin-2-one(Compound 26)

Step 1: Preparation of1-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methyl]piperidin-2-one

To a solution of piperidin-2-one (38 mg, 0.383 mmol) in DMF (1 mL) wasadded NaH (60% dispersion in mineral oil, 24 mg, 0.611 mmol) and themixture was stirred for 20 min. Intermediate 1 (30 mg, 0.122 mmol) wasthen added and the reaction mixture was stirred for 2 h at rt. Themixture was quenched with water and concentrated under reduced pressure.The residue was diluted with saturated NaHCO₃ (10 mL) and EtOAc (30 mL),and the aqueous layer was extracted with EtOAc (3×10 mL). The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated underreduced pressure to afford the title compound, which was used in thenext step without further purification. MS (ESI) [M+H]+ 308.1/310.1.

Step 2: Preparation of Compound 26

A solution of1-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methyl]piperidin-2-one (38 mg,0.122 mmol) and1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(prepared using the procedure described in US20130053362, 39.5 mg, 0.159mmol) in DME (2 mL) and water (0.1 mL) was degassed for 10 min. Cs₂CO₃(83 mg, 0.256 mmol) and Pd(PPh₃)₄ (14 mg, 0.012 mmol) were then addedand the mixture was degassed for another 10 min. The resulting mixturewas then heated at 85° C. for 2 h. The mixture was cooled to rt and wasdiluted with saturated NaHCO₃ (10 mL) and EtOAc (30 mL). The layers wereseparated and the aqueous layer was extracted with EtOAc (3×10 mL). Thecombined organic layers were dried over MgSO₄, filtered, andconcentrated under reduced pressure. The material was purified by flashchromatography on silica gel using a mixture of EtOAc in hexane aseluent, followed by preparative HPLC to provide Compound 26 (7 mg, 16%)as a solid. ¹H NMR (500 MHz, CDCl₃) δ 8.89 (s, 1H), 7.77 (d, J=9.3 Hz,1H), 7.66 (s, 1H), 7.51 (d, J=20.4 Hz, 1H), 7.48 (d, J=2.4 Hz, 1H), 7.41(dd, J=9.3, 1.6 Hz, 1H), 4.95 (s, 2H), 3.67 (s, 3H), 3.33-3.19 (m, 2H),2.50-2.36 (m, 2H), 2.26 (s, 3H), 1.90-1.58 (m, 4H). MS (ESI) [M+H]⁺351.2.

Example 27:5-(3-anilinoimidazo[1,2-a]pyridin-6-yl)-1,3-dimethyl-pyridin-2-one(Compound 30)

Step 1: Preparation of 6-bromo-N-phenyl-imidazo[1,2-a]pyridin-3-amine

To a solution of 5-bromopyridin-2-amine (1.0 g, 5.78 mmol) in DCE (20ml) and MeOH (10 mL) was added glyoxylic acid monohydrate (638.4 mg,6.94 mmol) and the mixture was stirred at rt for 30 min. To thesolution, phenyl isonitrile (1.16 g, 11.28 mmol) was added and thereaction mixture was stirred at rt for 48 h. The mixture was dilutedwith DCM (20 mL), treated with solid NaHCO₃ (2.5 g), then activatedcharcoal and stirred at rt for 15 min. The mixture was filtered througha plug of Celite™ and the filtrate was concentrated under reducedpressure. The material was purified by flash chromatography on silicausing a mixture of MeOH in DCM as eluent and then further trituratedwith Et₂O and hexane to afford the title compound (935 mg, 56%) as asolid. ¹H NMR (500 MHz, DMSO) b 8.17 (dd, J=1.9, 0.9 Hz, 1H), 8.05 (s,1H), 7.57 (dd, J=9.5, 0.8 Hz, 1H), 7.51 (d, J=0.6 Hz, 1H), 7.33 (dd,J=9.5, 1.9 Hz, 1H), 7.16 (dd, J=8.5, 7.4 Hz, 2H), 6.80-6.72 (m, 1H),6.64-6.57 (m, 2H). MS (ESI) [M+H]⁺ 288.1/290.1.

Step 2: Preparation of Compound 30

To a solution of 6-bromo-N-phenyl-imidazo[1,2-a]pyridin-3-amine (102.3mg, 0.355 mmol) in a mixture of DME (2 mL) and water (0.2 mL), wereadded1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(US2013/0053362; 106.13 mg, 0.426 mmol), Cs₂CO₃ (289 mg, 0.888 mmol) andPd(PPh₃)₄ (41.2 mg, 0.035 mmol) and the resulting mixture was degassedwith N₂ for 5 min and then heated to 100° C. in a sealed tube for 18 h.The mixture was cooled to rt and diluted with EtOAc (10 mL) and water(10 mL). The organic phase was separated, dried over MgSO₄, filtered andconcentrated under reduced pressure. The material was purified by flashchromatography on silica gel using a mixture MeOH in DCM as eluent,followed by preparative HPLC purification to afford Compound 30 (18.8mg, 16%) as a solid. ¹H NMR (500 MHz, CDCl₃) δ 7.90 (dd, J=1.8, 0.9 Hz,1H), 7.67 (dd, J=9.3, 0.9 Hz, 1H), 7.56 (d, J=0.7 Hz, 1H), 7.37 (dd,J=2.6, 1.2 Hz, 1H), 7.32 (s, 1H), 7.29 (dd, J=9.3, 1.9 Hz, 1H),7.24-7.19 (m, 2H), 6.88 (m, 1H), 6.62-6.57 (m, 2H), 5.56 (s, 1H), 3.60(s, 3H), 2.18 (s, 3H). MS (ESI) [M+H]⁺ 331.2.

Example 28: 1,3-dimethyl-5-[3-(2,2,2-trifluoroethoxymethyl)imidazo[1,2-a]pyridin-6-yl]pyridin-2-one (Compound 34)

Step 1: Preparation of 6-bromo-3-(2,2,2-trifluoroethoxymethyl)imidazo[1,2-a]pyridine

To a solution of 2,2,2-trifluoroethanol (408.95 mg, 4.07 mmol) in DMF (5mL) at 0° C. was added NaH (162.9 mg, 4.07 mmol) and the mixture wasstirred for 10 min. To the mixture, Intermediate 1 (100.0 mg, 0.407 mol)and DIPEA (0.142 mL, 0.815 mmol) in DMF (2 mL) were added and thereaction mixture was stirred at rt for 4 h. The mixture was poured intowater (20 mL) and the aqueous layer was extracted with EtOAc (3×10 mL).The combined organic layers were dried over MgSO₄, filtered andconcentrated under reduced pressure. The material was purified by flashchromatography on silica gel using a mixture of EtOAc in hexane aseluent to afford the title compound (102.2 mg, 81%) as a solid. ¹H NMR(500 MHz, CDCl₃) δ 8.32 (dd, J=1.8, 0.8 Hz, 1H), 7.63 (s, 1H), 7.55 (dd,J=9.5, 0.8 Hz, 1H), 7.33 (dd, J=9.5, 1.9 Hz, 1H), 4.97 (s, 2H), 3.79 (q,J=8.6 Hz, 2H). MS (ESI) [M+H]⁺ 309.1/311.1.

Step 2: Preparation of Compound 34

Pd(PPh₃)₄ (9 mg, 0.008 mmol) was added to a degassed solution of6-bromo-3-(2,2,2-trifluoroethoxymethyl)imidazo[1,2-a]pyridine (22 mg,0.078 mmol), and1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(prepared as in US2013/0053362; 25 mg, 0.102 mmol) and Cs₂CO₃ (64 mg,0.196 mmol) in a mixture of DME (3 mL) and water (0.3 mL) under N₂. Theresulting reaction mixture was heated to 80° C. for 20 h and then cooledto rt. The mixture was filtered through Celite™ and washed with EtOAc(100 mL). To the filtrate, saturated NaHCO₃ (25 mL) was added and theaqueous phase was extracted with EtOAc (3×50 mL). The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The material was purified by flash chromatography on silicagel using a mixture of EtOAc in hexane as eluent, followed bypreparative HPLC to provide Compound 34 (3.8 mg, 15%) as a solid. ¹H NMR(500 MHz, CDCl₃) δ 8.21 (s, 1H), 7.74-7.65 (m, 2H), 7.45 (d, J=1.3 Hz,1H), 7.39 (d, J=2.5 Hz, 1H), 7.35 (dd, J=9.3, 1.8 Hz, 1H), 5.04 (s, 2H),3.83 (q, J=8.7 Hz, 2H), 3.65 (s, 3H), 2.25 (s, 3H). MS (ESI) [M+H]⁺352.3.

Example 29:6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-N-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-a]pyridine-3-sulfonamide(Compound 42)

Step 1: Preparation of6-bromo-N-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-a]pyridine-3-sulfonamide

TEA (0.71 mL, 5.0754 mmol) was added to a room temperature stirredsolution of tetrahydro-2H-pyran-4-amine hydrochloride (0.349 g, 2.5377mmol) in DCM (5 mL), followed by the addition of a solution ofIntermediate 3 (0.5 g, 1.6918 mmol) in DCM (5 mL). The reaction mixturewas stirred for 2 h and, after completion, was concentrated underreduced pressure. The product obtained was purified by silica gel columnchromatography using a gradient of 50-70% ethyl acetate in hexane aseluent. The fractions were combined and concentrated to afford the titlecompound (0.2 g, 33%) as a semisolid (MH⁺ 360.04).

Step 2: Preparation of Compound 42

A stirred solution of6-bromo-N-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-a]pyridine-3-sulfonamide(0.2 g, 0.5552 mmol) and1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one(0.208 g, 0.8328 mmol) in 1,4-dioxane (5 mL) was purged with nitrogenfor 20 min, followed by the addition of sodium carbonate (0.177 g,1.6656 mmol) in water (0.5 mL). The reaction mixture was purged againwith nitrogen for 20 min. Pd(PPh₃)₄ (0.032 g, 0.0277 mmol) was thenadded and the reaction mixture was heated at 100° C. for 6 h. Thereaction mixture was concentrated under reduced pressure and the crudeproduct was purified by silica gel chromatography using 2-3% methanol inDCM as eluent. Fractions were combined and concentrated to affordCompound 42 (0.060 g, 27%) as a solid. ¹H NMR (400 MHz, DMSO) δ 8.67 (s,1H), 8.61 (d, J=7.6 Hz, 1H), 8.11 (s, 1H), 8.09 (s, 1H), 7.9 (d, J=9.6Hz, 1H), 7.83 (dd, J=1.6 and 9.6 Hz, 1H), 7.78 (d, J=1.2 Hz, 1H),3.69-3.66 (m, 2H), 3.56 (s, 3H), 3.22-3.16 (m, 3H), 2.14 (s, 3H),1.39-1.27 (m, 4H), MH⁺ 403.29.

Example 30:6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-N-(tetrahydro-2H-pyran-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide(Compounds 43 & 44)

Step 1: Preparation of6-bromo-N-(tetrahydro-2H-pyran-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide

TEA (1.3 mL, 9.1358 mmol) was added to a room temperature stirredsolution of tetrahydro-2H-pyran-3-amine hydrochloride (0.629 g, 4.5679mmol) in DCM (5 mL), followed by the addition of a solution ofIntermediate 3 (0.9 g, 3.0453 mmol) in DCM (5 mL). The reaction mixturewas stirred at rt for 2 h and, after completion of reaction, wasconcentrated under reduced pressure. The product obtained was purifiedby silica gel chromatography using a gradient of 50-70% ethyl acetate inhexane as eluent. Fractions were combined and concentrated to afford thetitle compound (0.32 g, 27%) as a semisolid. MH⁺ 362.45.

Step 2: Preparation of Compounds 43 and 44

A stirred solution of6-bromo-N-(tetrahydro-2H-pyran-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide(0.32 g, 0.8883 mmol) and1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one(0.332 g, 1.3325 mmol) in 1,4-dioxane (5 mL) was purged with nitrogenfor 20 min, followed by the addition of sodium carbonate (0.283 g, 2.665mmol) in water (0.5 mL). The reaction mixture was purged with nitrogenfor another 20 min. Pd(PPh₃)₄ (0.051 g, 0.0444) was the added and thereaction mixture was heated at 100° C. for 6 h. The reaction mixture wasconcentrated under reduced pressure and the crude product was purifiedby silica gel chromatography using 2-3% methanol in DCM as eluent.Fractions were combined and concentrated to afford the title compound inracemic form (0.125 g), which was further purified by chiral preparativeHPLC (Chiralpak™ IC (250*21) mm, 5μ Column, flow 15.0 mL/min, isocratic30% n-Hexane in IPA: Methanol (70:30)) to afford two isomers in separatefractions: Fraction 1 (Compound 43): 0.025 g and Fraction 2 (Compound44): 0.030 g.

Compound 43: Retention Time=9.02: ¹H NMR (400 MHz, DMSO) δ ppm 8.69 (s,1H), 8.65 (bs, 1H), 8.11 (s, 2H), 7.90 (d, J=9.6 Hz, 1H), 7.83 (dd,J=1.6 and 9.6 Hz, 1H), 7.79 (d, J=1.2 Hz, 1H), 3.55-3.53 (m, 4H),3.48-3.42 (m, 1H), 3.26-3.21 (m, 1H), 3.06-3.00 (m, 2H), 2.14 (s, 3H),1.56-1.53 (m, 1H), 1.49-1.46 (m, 1H), 1.37-1.26 (m, 2H), M+1: 403.29.

Compound 44: Retention Time=11.09: ¹H NMR (400 MHz, DMSO) δ ppm 8.69 (s,1H), 8.65 (bs, 1H), 8.11 (s, 1H), 8.10 (s, 1H), 7.90 (d, J=9.2 Hz, 1H),7.83 (dd, J=1.6 and 9.2 Hz, 1H), 7.79 (d, J=1.6 Hz, 1H), 3.56-3.53 (m,4H), 3.45-3.42 (m, 1H), 3.26-3.21 (m, 1H), 3.04-3.02 (m, 2H), 2.14 (s,3H), 1.56-1.53 (m, 1H), 1.49-1.46 (m, 1H), 1.35-1.26 (m, 2H), MH⁺:403.29.

Example 31:(R)-1,3-dimethyl-5-(3-((2-methylpyrrolidin-1-yl)sulfonyl)imidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one(Compound 45)

Step 1: Preparation of(R)-6-bromo-3-((2-methylpyrrolidin-1-yl)sulfonyl)imidazo[1,2-a]pyridine

TEA (0.42 mL, 3.0453 mmol) was added to a room temperature stirredsolution of (R)-2-methylpyrrolidine hydrochloride (0.185 g, 1.5226 mmol)in DCM (5 mL), followed by the addition of a solution of Intermediate 3(0.3 g, 1.0151 mmol) in DCM (5 mL). The reaction mixture was stirred atrt for 2 h and, after completion, was concentrated under reducedpressure. The product obtained was purified by silica gel chromatographyusing a gradient of 50-70% ethyl acetate in hexane as eluent. Thefractions were combined and concentrated to afford the title compound(0.07 g, 20%). MH⁺ 346.19.

Step 2: Preparation of Compound 45

A stirred solution of(R)-6-bromo-3-((2-methylpyrrolidin-1-yl)sulfonyl)imidazo[1,2-a]pyridine(0.070 g, 0.2033 mmol) and1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one(0.076 g, 0.3050 mmol) in 1,4-dioxane (5 mL) was purged with nitrogenfor 20 min, followed by the addition of sodium carbonate (0.065 g, 0.61mmol) in water (0.5 mL). The reaction mixture was purged with nitrogenfor another 20 min. Pd(PPh₃)₄ (0.012 g, 0.0101 mmol) was then added andthe reaction mixture was heated at 100° C. for 6 h. The reaction mixturewas concentrated under reduced pressure and the crude product waspurified by silica gel chromatography using 2-3% methanol in DCM aseluent. Fractions were combined and concentrated to afford Compound 45(0.025 g, 16%). ¹H NMR (400 MHz, DMSO) δ 8.77 (s, 1H), 8.23 (s, 1H),8.05 (d, J=2.4 Hz, 1H), 7.90 (d, J=9.2 Hz, 1H), 7.80 (dd, J=1.6 and 2Hz, 1H), 7.63 (d, J=1.2 Hz, 1H), 3.84-3.80 (m, 1H), 3.55 (s, 3H),3.43-3.37 (m, 1H), 3.24-3.17 (m, 1H), 2.11 (s, 3H), 1.84-1.75 (m, 2H),1.58-1.48 (m, 2H), 1.24 (d, J=6.4 Hz, 3H). MH⁺ 387.34.

Example 32:(S)-1,3-dimethyl-5-(3-((2-methylpyrrolidin-1-yl)sulfonyl)imidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one(Compound 46)

Step 1: Preparation of(S)-6-bromo-3-((2-methylpyrrolidin-1-yl)sulfonyl)imidazo[1,2-a]pyridine

TEA (0.71 mL, 5.0754 mmol) was added to a room temperature stirredsolution of (S)-2-methylpyrrolidine hydrochloride (0.309 g, 2.5377 mmol)in DCM (5 mL), followed by the addition of a solution of Intermediate 3(0.5 g, 1.6918 mmol) in DCM (5 mL). The reaction mixture was stirred atrt for 2 h and, after completion, was concentrated under reducedpressure. The product obtained was purified by silica gel chromatographyusing a gradient of 50-70% ethyl acetate in hexane as eluent. Fractionswere combined and concentrated to afford the title compound (0.1 g, 17%)as a semisolid. MH⁺ 346.0.

Step 2: Preparation of Compound 46

A stirred solution of(S)-6-bromo-3-((2-methylpyrrolidin-1-yl)sulfonyl)imidazo[1,2-a]pyridine(0.1 g, 0.2905 mmol) and1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one(0.109 g, 0.4357 mmol) in 1,4-dioxane (5 mL) was purged with nitrogenfor 20 min, followed by the addition of sodium carbonate (0.092 g,0.8715 mmol) in water (0.5 mL). The reaction mixture was again purgedwith nitrogen for 20 min. Pd(PPh₃)₄ (0.017 g, 0.0145 mmol) was thenadded and the reaction mixture was heated at 100° C. for 6 h. Thereaction mixture was concentrated under reduced pressure and the crudeproduct was purified by silica gel chromatography using 2-3% methanol inDCM as eluent. Fractions were combined and concentrated to dryness toafford 0.1 g, which product was repurified by preparative HPLC using 30%acetonitrile in water with ammonium acetate to afford Compound 46 (0.015g, 13%) as a solid. ¹H NMR (400 MHz, DMSO) δ 8.79 (s, 1H), 8.23 (s, 1H),8.05 (d, J=2.8 Hz, 1H), 7.90 (dd, J=5.6 Hz and 0.8 Hz, 1H), 7.80 (dd,J=9 9.6 Hz and 2 Hz, 1H), 7.63 (dd, J=1.2 and 2.4 Hz, 1H), 3.84-3.80 (m,1H), 3.55 (s, 3H), 3.43-3.37 (m, 1H), 3.24-3.17 (m, 1H), 2.11 (s, 3H),1.87-1.73 (m, 2H), 1.58-1.48 (m, 2H), 1.24 (d, J=6.4 Hz, 3H). MH⁺387.34.

Example 33:6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-N-methyl-N-(tetrahydrofuran-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide(Compounds 47 and 48)

Step 1: Preparation of6-bromo-N-methyl-N-(tetrahydrofuran-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide

TEA (1.5 mL, 10.963 mmol) was added to a room temperature stirredsolution of N-methyltetrahydrofuran-3-amine hydrochloride (0.754 g,5.4815 mmol) in DCM (5 mL), followed by the addition of a solution ofIntermediate 3 (1.08 g, 3.6543 mmol) in DCM (5 mL). The reaction mixturewas stirred at rt for 20 h and, after completion, was concentrated underreduced pressure. The product obtained was purified by silica gelchromatography using a gradient of 50-70% ethyl acetate in hexane aseluent. The fractions were combined and concentrated to dryness toafford the title compound (0.24 g, 18%) as a semisolid. MH⁺ 360.14.

Step 2: Preparation of Compounds 47 and 48

A stirred solution of6-bromo-N-methyl-N-(tetrahydrofuran-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide(0.24 g, 0.6662 mmol) and1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one(0.249 g, 0.9993 mmol) in 1,4-dioxane (5 mL) was purged with nitrogenfor 20 min, followed by the addition of sodium carbonate (0.212 g,1.9987 mmol) in water (0.5 mL). The reaction mixture was again purgedwith nitrogen for 20 min. Pd(PPh₃)₄ (0.038 g, 0.0333) was then added andthe reaction mixture was heated at 100° C. for 6 h. The reaction mixturewas concentrated under reduced pressure and the crude product waspurified by silica gel chromatography using 2-3% methanol in DCM aseluent. Fractions were combined and concentrated to dryness to affordthe title compound in racemic form (0.070 g) which was further purifiedby chiral preparative HPLC (ChiralCEL™ OJ-H (250*20)mm, 5μ Column, flow70.0 mL/min, isocratic 80% liquid CO₂ and 20% IPA) to afford two isomersin separate fractions: Fraction 1 (Compound 47): 0.018 g and Fraction 2(Compound 48): 0.025 g.

Compound 47: Retention Time=8.43: 1H NMR (400 MHz, DMSO) δ ppm 8.66 (s,1H), 8.22 (s, 1H), 8.05 (d, J=2.0 Hz, 1H), 7.92 (d, J=9.2 Hz, 1H), 7.80(dd, J=1.6 and 2 Hz, 1H), 7.68 (d, J=1.2 Hz, 1H), 4.79-4.74 (m, 1H),3.81-3.75 (m, 1H), 3.55 (s, 3H), 3.54-3.51 (m, 2H), 3.47-3.41 (m, 1H),2.75 (s, 3H), 2.12 (s, 3H), 1.90-1.81 (m, 1H), 1.59-1.51 (m, 1H), M+1:403.2

Compound 48: Retention Time=10.17: 1H NMR (400 MHz, DMSO) δ ppm 8.67 (s,1H), 8.22 (s, 1H), 8.04 (d, J=2.8 Hz, 1H), 7.92 (d, J=9.6 Hz, 1H), 7.80(dd, J=1.6 and 2 Hz, 1H), 7.67 (d, J=1.6 Hz, 1H), 4.79-4.73 (m, 1H),3.80-3.75 (m, 1H), 3.54 (s, 3H), 3.53-3.51 (m, 2H), 3.46-3.39 (m, 1H),2.75 (s, 3H), 2.11 (s, 3H), 1.89-1.81 (m, 1H), 1.59-1.50 (m, 1H), M+1:403.2

Example 34:5-(3-(cyclopentylsulfonyl)imidazo[1,2-a]pyridin-6-yl)-1,3-dimethylpyridin-2(1H)-one(Compound 49)

Step 1: Preparation of 6-bromo-3-(cyclopentylthio)imidazo[1,2-a]pyridine

Copper(I) iodide (0.024 g, 0.13 mmol) and 6-bromoimidazo[1,2-a]pyridine(0.5 g, 2.53 mmole) were charged to an oven dried vial. The vial wasevacuated and back-filled with oxygen. Under a counter-flow of oxygen,cyclopentanethiol (0.42 g, 4.06 mmol) was added, followed by DMSO (3 mL)using a syringe. The vial was placed in a pre-heated oil bath at 120° C.and the reaction mixture was stirred vigorously for 28 h at thistemperature under oxygen. After completion, the reaction mixture wasallowed to cool to room temperature and was then diluted with water (50mL) and extracted with ethyl acetate (30 mL×3). The combined ethylacetate layer was washed with brine (30 mL), dried over anhydrous Na₂SO₄and concentrated under vacuum to afford the title compound (0.3 g, 14%)as a semisolid. This product was used in the next step without furtherpurification. MH⁺ 297.0.

Step 2: Preparation of6-bromo-3-(cyclopentylsulfonyl)imidazo[1,2-a]pyridine

To a suspension of 6-bromo-3-(cyclopentylthio)imidazo[1,2-a]pyridine(0.3 g, 1.01 mmol) in DCM (6 mL) was added m-CPBA (0.35 g, 2.02 mmol)and the resulting reaction mixture was stirred at room temperature for 3h. The reaction mixture was then diluted with DCM (50 mL), washed withwater (40 mL×2) and brine (30 mL), dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford the title compound (0.21g, 29%) as an oil: MH⁺: 331.0. The product was used for the next stepwithout further purification.

Step 3: Preparation of Compound 49

A stirred solution of6-bromo-3(cyclopentylsulfonyl)imidazo[1,2-a]pyridine (0.21 g, 0.64 mmol)and1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one(0.21 g, 0.83 mmol) in 1,4-dioxane (4 mL) was purged with nitrogen for10 minutes, followed by the addition of sodium carbonate (0.21 g, 1.92mmol) in water (0.5 mL). The reaction mixture was again purged withnitrogen for 10 min. Pd(PPh₃)₄ (0.037 g, 0.032 mmol) was then added andthe reaction mixture was heated at 90° C. for 6 h. The solvent wasevaporated under reduced pressure and water (80 mL) was added. Theproduct was extracted using ethyl acetate (40 mL×3). The combinedorganic layer was washed with brine (50 mL), dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The product obtained waspurified by silica gel flash chromatography using 1.5 to 2% methanol inDCM as eluent. Fractions were combined and concentrated to give 0.11 gof product, which was triturated with a methanol:diethyl ether (0.5 mL:8 mL) and with diethyl ether (5 mL×2) to afford Compound 49 (0.032 g,29%) as a solid. ¹H NMR (400 MHz, DMSO) δ 8.76 (s, 1H), 8.24 (s, 1H),8.08 (d, J=2 Hz, 1H), 7.94 (d, J=9.2 Hz, 1H), 7.83 (dd, J=1.2 and 9.6Hz, 1H), 7.71 (s, 1H), 4.10-4.02 (m, 1H), 3.55 (s, 3H), 2.12 (s, 3H),1.94-1.87 (m, 4H), 1.67-1.58 (m, 4H); MH⁺372.29.

Example 35:(S)-5-(3-((3-methoxypyrrolidin-1-yl)sulfonyl)imidazo[1,2-a]pyridin-6-yl)-1,3-dimethylpyridin-2(1H)-one(Compound 50)

Step 1: Preparation of(S)-6-bromo-3-((3-methoxypyrrolidin-1-yl)sulfonyl)imidazo[1,2-a]pyridine

TEA (0.57 mL, 4.0606 mmol) was added to a room temperature stirredsolution of (S)-3-methoxypyrrolidine hydrochloride (0.279 g, 2.0303mmol) in DCM (5 mL), followed by the addition of a solution ofIntermediate 3 (0.4 g, 1.3535 mmol) in DCM (5 mL). The reaction mixturewas stirred at rt for 2 h and, after completion, was evaporated underreduced pressure. The product obtained was purified by silica gelchromatography using a gradient of 50-70% ethyl acetate in hexane aseluent. The fractions were combined and concentrated to afford the titlecompound (0.2 g, 41%) as a semisolid. MH⁺360.14.

Step 2: Preparation of Compound 50

A stirred solution of(S)-6-bromo-3-((3-methoxypyrrolidin-1-yl)sulfonyl)imidazo[1,2-a]pyridine(0.2 g, 0.5552 mmol) and1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one(0.207 g, 0.8328 mmol) in 1,4-dioxane (5 mL) was purged with nitrogenfor 20 min, followed by the addition of sodium carbonate (0.177 g,1.6656 mmol) in water (0.5 mL). The reaction mixture was purged againwith nitrogen for 20 min. Pd(PPh₃)₄ (0.032 g, 0.0278 mmol) was thenadded and the reaction mixture was heated at 100° C. for 6 h. Thereaction mixture was concentrated under reduced pressure and the crudeproduct was purified by silica gel chromatography using 2-3% methanol inDCM as eluent. Fractions were combined and concentrated to affordCompound 50 (0.038 g, 17%) as a solid. ¹H NMR (400 MHz, DMSO) δ 8.79 (s,1H), 8.20 (s, 1H), 8.05 (d, J=2.8 Hz, 1H), 7.90 (d, J=9.2 Hz, 1H), 7.79(dd, J=1.6 and 9.6 Hz, 1H), 7.66 (d, J=1.2 Hz, 1H), 3.85-3.84 (m, 1H),3.55 (s, 3H), 3.44-3.35 (m, 3H), 3.25-3.21 (m, 1H), 2.93 (s, 3H), 2.12(s, 3H), 1.89-1.86 (m, 2H). MH⁺403.29.

Example 36: (R)-5-(3-((3-methoxypyrrolidin-1-yl) sulfonyl)imidazo[1,2-a]pyridin-6-yl)-1,3-dimethylpyridin-2(1H)-one (Compound 51)

Step 1: Preparation of(R)-6-bromo-3-((3-methoxypyrrolidin-1-yl)sulfonyl)imidazo[1,2-a]pyridine

TEA (0.71 mL, 5.0755 mmol) was added to a room temperature stirredsolution of (S)-3-methoxypyrrolidine hydrochloride (0.349 g, 2.5377mmol) in DCM (5 mL), followed by the addition of a solution ofIntermediate 3 (0.5 g, 1.6918 mmol) in DCM (5 mL). The reaction mixturewas stirred at rt for 2 h and, after completion, was concentrated underreduced pressure. The product obtained was purified by silica gelchromatography using a gradient of 50-70% ethyl acetate in hexane aseluent. The fractions were combined and concentrated to afford the titlecompound (0.2 g, 33%) as a semisolid. MH⁺360.14

Step 2: Preparation of Compound 51

A stirred solution of(R)-6-bromo-3-((3-methoxypyrrolidin-1-yl)sulfonyl)imidazo[1,2-a]pyridine(0.2 g, 0.5552 mmol) and1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one(0.207 g, 0.8328 mmol) in 1,4-dioxane (5 mL) was purged with nitrogenfor 20 min, followed by addition of sodium carbonate (0.177 g, 1.6656mmol) in water (0.5 mL). The reaction mixture was again purged withnitrogen for 20 min. Pd(PPh₃)₄ (0.032 g, 0.0278 mmol) was then added andthe reaction mixture was heated at 100° C. for 6 h. The reaction mixturewas concentrated under reduced pressure and the crude product waspurified by silica gel chromatography using 2-3% methanol in DCM aseluent. Fractions were combined and concentrated to dryness to affordCompound 51 (0.045 g, 20%) as a solid. ¹H NMR (400 MHz, DMSO) δ 8.79 (s,1H), 8.20 (s, 1H), 8.05 (d, J=2 Hz, 1H), 7.90 (d, J=9.6 Hz, 1H),7.80-7.78 (m, 1H), 7.67 (s, 1H), 3.84-3.83 (m, 1H), 3.55 (s, 3H),3.44-3.35 (m, 3H), 3.25-3.19 (m, 1H), 2.93 (s, 3H), 2.12 (s, 3H),1.89-1.86 (m, 2H). MH⁺403.34.

Example 37:6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-N-(tetrahydrofuran-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide (Compounds 52 and 53)

Step 1: Preparation of6-bromo-N-(tetrahydrofuran-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide

DIPEA (0.7 mL, 4.06 mmol) was added to a room temperature stirredsolution of 3-amino tetrahydrofuran hydrochloride (0.251 g, 2.03 mmol)in DMSO (5 mL), followed by the addition of a solution of Intermediate 3(0.4 g, 1.35 mmol) in DMSO (5 mL). The reaction mixture was heated at100° C. under microwave irradiation for 40 min. After completion, thereaction mixture was allowed to cool to rt and was diluted with ethylacetate (250 mL) and washed with water (150 mL×3). The organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The product obtained was purified by silica gel chromatographyusing a gradient of 70-100% ethyl acetate in hexane as eluent. Thefractions were combined and concentrated to afford the title compound(0.15 g, 32%) as a semisolid. M⁺ 348.14.

Step 2: Preparation of Compounds 52 and 53

A stirred solution of6-bromo-N-(tetrahydrofuran-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide(0.15 g, 0.43 mmol) and1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one(0.162 g, 0.65 mmol) in 1,4-dioxane (5 mL) was purged with nitrogen for20 min, followed by the addition of sodium carbonate (0.138 g, 1.30mmol) in water (0.5 mL). The reaction mixture was again purged withnitrogen for 20 min. Pd(PPh₃)₄ (0.025 g, 0.02) was then added and thereaction mixture was heated at 100° C. for 6 h. The reaction mixture wasconcentrated under reduced pressure and the crude product was purifiedby silica gel chromatography using 2-3% methanol in DCM as eluent.Fractions were combined and concentrated to afford the title compound inracemic form (0.080 g), which was further purified by chiral preparativeHPLC (Chiralpak™ AD-H (250*21) mm, 5μ Column, flow 70.0 ml/min,isocratic (A) liquid CO₂ (B) 0.3% DEA in MeOH, (A):(B)=60:40) to affordtwo isomers in separate fractions: Fraction 1 (Compound 52): 0.015 g andFraction 2 (Compound 53): 0.040 g for a total of 33% yield.

Compound 52: Retention Time=4.17: ¹H NMR (400 MHz, Methanol-d₄) δ ppm8.79 (s, 1H), 8.14 (s, 1H), 8.00 (d, J=2.4 Hz, 1H), 7.87-7.81 (m, 3H),3.92-3.87 (m, 1H), 3.81 (q, J=7.6 Hz, 1H), 3.70 (s, 3H), 3.68-3.65 (m,2H), 3.43 (dd, J=3.6 and 9.2 Hz, 1H), 2.25 (s, 3H), 2.08-1.99 (m, 1H),1.67-1.59 (m, 1H), M+1: 389.24

Compound 53: Retention Time=4.79: ¹H NMR (400 MHz, Methanol-d₄) δ ppm8.79 (s, 1H), 8.14 (s, 1H), 8.00 (d, J=2.4 Hz, 1H), 7.87-7.81 (m, 3H),3.93-3.87 (m, 1H), 3.81 (q, J=7.6 Hz, 1H), 3.70 (s, 3H), 3.68-3.65 (m,2H), 3.43 (dd, J=3.6 and 9.2 Hz, 1H), 2.25 (s, 3H), 2.08-1.99 (m, 1H),1.67-1.59 (m, 1H), M+1: 389.24

Example 38:1,3-dimethyl-5-[2-methyl-3-(2-pyridylmethyl)imidazo[1,2-a]pyridin-6-yl]pyridin-2-one(Compound 54)

Step 1: Preparation of(6-bromo-2-methyl-imidazo[1,2-a]pyridin-3-yl)-(2-pyridyl) methanone

To a suspension of 5-bromopyridin-2-amine (357.0 mg, 2.06 mmol) in MeOH(7 mL) was added N,N-dimethylacetamide dimethyl acetal (305.36 mg, 2.06mmol) and the reaction mixture was heated to 80° C. for 18 h. Themixture was cooled to rt and concentrated under reduced pressure. Theresidue was diluted with EtOAc (10 mL) and then washed with saturatedNaHCO₃ (10 mL). The organic layer was dried over MgSO₄, filtered andconcentrated under reduced pressure. The material was dissolved intoluene (7 mL) and 2-bromo-1-(2-pyridyl)ethanone hydrobromide (644.1 mg,2.06 mmol) was added followed with DIPEA (0.36 mL, 2.06 mmol) and thereaction mixture was heated in a sealed tube at 140° C. for 30 min. Themixture was cooled to rt, diluted with EtOAc (10 mL) and washed withwater (2×30 mL). The organic layer was dried over MgSO₄, filtered andconcentrated under reduced pressure. The material was triturated withEt₂O and hexane to afford the title compound (113.0 mg, 17%) as a solid.¹H NMR (500 MHz, CDCl₃) δ 9.85-9.73 (m, 1H), 8.83 (dd, J=4.3, 1.6 Hz,2H), 7.61 (dt, J=20.0, 5.6 Hz, 2H), 7.47 (dd, J=4.3, 1.6 Hz, 2H), 2.14(s, 3H). MS (ESI) [M+H]⁺ 316.1/318.1.

Step 2: Preparation of1,3-dimethyl-5-[2-methyl-3-(pyridine-2-carbonyl)imidazo[1,2-a]pyridin-6-yl]pyridin-2-one

To a solution of(6-bromo-2-methyl-imidazo[1,2-a]pyridin-3-yl)-(2-pyridyl)methanone(327.0 mg, 1.034 mmol) in a mixture of DME (3 mL) and water (0.3 mL)were added1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(prepared as in US20130053362, 309.2 mg, 1.24 mmol), Cs₂CO₃ (842.5 mg,2.59 mmol) and Pd(PPh₃)₄ (119.9 mg, 0.103 mmol). The reaction mixturewas degassed with N₂ for 5 min and then heated to 100° C. for 18 h. Themixture was cooled to rt and diluted with EtOAc (10 mL) and water (10mL). The phases were separated and the organic layer was dried overMgSO₄, filtered and concentrated under reduced pressure. The materialwas purified by flash chromatography on silica gel using a gradient(0-20%) of MeOH in DCM as eluent to afford the title compound (213 mg,57%) as a solid. ¹H NMR (500 MHz, CDCl₃) δ 9.66 (dd, J=1.9, 0.9 Hz, 1H),8.72 (ddd, J=4.8, 1.7, 1.0 Hz, 1H), 7.94 (td, J=7.7, 1.7 Hz, 1H), 7.81(dt, J=7.8, 1.1 Hz, 1H), 7.69 (dd, J=9.2, 0.9 Hz, 1H), 7.59-7.42 (m,4H), 3.64 (s, 3H), 2.24 (s, 3H), 2.15 (s, 3H). MS (ESI) [M+H]⁺ 359.3.

Step 3: Preparation of Compound 54

A solution of1,3-dimethyl-5-[2-methyl-3-(pyridine-2-carbonyl)imidazo[1,2-a]pyridin-6-yl]pyridin-2-one(213.0 mg, 0.59 mmol), hydrazine hydrate (1.72 mL, 19.39 mmol) and KOH(266.7 mg, 4.75 mmol) in ethylene glycol (4 mL) was heated to 150° C. ina sealed vial for 20 h. The solution was cooled to rt and diluted withDCM (10 mL) and H₂O (10 mL). The aqueous layer was extracted with DCM(3×10 mL). The combined organic layers were dried over MgSO₄, filteredand concentrated under reduced pressure. The material was purified bypreparative HPLC to afford Compound 54 (55 mg, 27%) as a solid. ¹H NMR(500 MHz, CDCl₃) δ 8.56 (d, J=4.4 Hz, 1H), 8.10 (s, 1H), 7.56 (m, 2H),7.36 (s, 1H), 7.28 (d, J=2.3 Hz, 1H), 7.19-7.15 (m, 2H), 7.00 (d, J=7.8Hz, 1H), 4.43 (s, 2H), 3.75 (s, 3H), 3.61 (s, 3H), 2.55 (s, 3H). MS(ESI) [M+H]⁺ 345.2.

Example 39:1,3-dimethyl-5-[2-methyl-3-(3-pyridylmethyl)imidazo[1,2-a]pyridin-6-yl]pyridin-2-one(Compound 55)

Step 1: Preparation of(6-bromo-2-methyl-imidazo[1,2-a]pyridin-3-yl)-(3-pyridyl) methanone

To a suspension of 5-bromopyridin-2-amine (362 mg, 2.092 mmol) in MeOH(5 mL) was added N,N-dimethylacetamide dimethyl acetal (309.6 mg, 2.09mmol) and the reaction mixture was heated to 80° C. for 18 h. Themixture was cooled to rt and concentrated under reduced pressure. Theresidue was diluted with EtOAc (10 mL) and the organic layer was washedwith saturated NaHCO₃ (10 mL). The organic layer was dried over MgSO₄,filtered and concentrated under reduced pressure. The residue (500 mg,2.07 mmol) was dissolved in toluene (10 mL) and2-bromo-1-(3-pyridyl)ethanone hydrobromide (580.2 mg, 2.07 mmol) wasadded, followed by DIPEA (0.37 mL, 2.07 mmol). The reaction mixture washeated at 140° C. for 10 min and then was cooled to rt in the oil bath.The mixture was then concentrated under reduced pressure and the residuewas dissolved in EtOAc (20 mL) with a minimum of MeOH. The organic layerwas washed with saturated NaHCO₃ (3×20 mL). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated under reducedpressure. The material was purified by flash chromatography on silicagel using a mixture of MeOH in DCM as eluent to afford the titlecompound (138 mg, 21%) as a solid. ¹H NMR (500 MHz, CDCl₃) δ 9.73 (dd,J=1.7, 1.0 Hz, 1H), 8.90-8.79 (m, 2H), 8.02-7.93 (m, 1H), 7.63-7.54 (m,2H), 7.49 (ddd, J=7.8, 4.9, 0.8 Hz, 1H), 2.20 (s, 3H). MS (ESI) [M+H]⁺316.1/318.1.

Step 2: Preparation of1,3-dimethyl-5-[2-methyl-3-(pyridine-3-carbonyl)imidazo[1,2-a]pyridin-6-yl]pyridin-2-one

To a solution of(6-bromo-2-methyl-imidazo[1,2-a]pyridin-3-yl)-(3-pyridyl)methanone (138mg, 0.436 mmol) in a mixture of DME (5 mL) and water (0.5 mL) were added1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(prepared as in US20130053362, 130.5 mg, 0.524 mmol), Cs₂CO₃ (355 mg,1.09 mmol) and Pd(PPh₃)₄ (50.62 mg, 0.044 mmol). The reaction mixturewas degassed with N₂ for 5 min and then heated in a sealed tube at 100°C. for 18 h. The mixture was cooled to rt, and then diluted with EtOAc(10 mL) and water (10 mL). The organic layer was dried over MgSO₄,filtered and concentrated under reduced pressure. The material wastriturated with Et₂O to afford the title compound (129 mg, 83%), whichwas used in the next step without further purification. ¹H NMR (500 MHz,CDCl₃) δ 9.67 (dd, J=1.9, 0.9 Hz, 1H), 8.87 (ddd, J=6.6, 3.5, 1.2 Hz,2H), 8.05-7.98 (m, 1H), 7.76-7.69 (m, 1H), 7.61 (dd, J=9.2, 1.9 Hz, 1H),7.54-7.45 (m, 3H), 3.66 (s, 3H), 2.25 (d, J=14.2 Hz, 6H). MS (ESI)[M+H]⁺ 359.3.

Step 3: Preparation of Compound 55

A solution of1,3-dimethyl-5-[2-methyl-3-(pyridine-3-carbonyl)imidazo[1,2-a]pyridin-6-yl]pyridin-2-one(129.0 mg, 0.36 mmol), hydrazine hydrate (1.04 mL, 11.75 mmol) and KOH(161.5 mg, 2.88 mmol) in ethylene glycol (1 mL) was heated to 150° C. ina sealed vial for 20 h. The solution was cooled to rt and diluted withDCM (10 mL) and water (10 mL). The phases were separated and the aqueouslayer was extracted with DCM (3×10 mL). The combined organic layers weredried over MgSO₄, filtered and concentrated under reduced pressure. Thematerial was purified by preparative HPLC to afford Compound 55 (45 mg,36%) as a solid. ¹H NMR (500 MHz, CDCl₃) δ 8.55-8.46 (m, 2H), 7.64-7.54(m, 2H), 7.35 (d, J=7.9 Hz, 1H), 7.29 (m, 1H), 7.25-7.14 (m, 3H), 4.29(s, 2H), 3.59 (s, 3H), 2.52 (s, 3H), 2.20 (s, 3H). MS (ESI) [M+H]⁺345.3.

Example 40:1,3-dimethyl-5-[2-methyl-3-(4-pyridylmethyl)imidazo[1,2-a]pyridin-6-yl]pyridin-2-one(Compound 56)

Step 1: Preparation of(6-bromo-2-methyl-imidazo[1,2-a]pyridin-3-yl)-(4-pyridyl) methanone

To a suspension of 5-bromopyridin-2-amine (357 mg, 2.06 mmol) in MeOH (7mL) was added N,N-dimethylacetamide dimethyl acetal (305.4 mg, 2.06mmol) and the reaction mixture was heated to 80° C. for 18 h. Themixture was cooled to rt and concentrated under reduced pressure. Theresidue was diluted in EtOAc (10 ml) and the organic layer was washedwith saturated NaHCO₃. The organic layer was dried over MgSO₄, filteredand concentrated under reduced pressure. The residue was diluted intoluene (7 mL) and 2-bromo-l-(4-pyridyl)ethanone hydrobromide (644.1 mg,2.06 mmol) was added followed by DIPEA (0.36 mL, 2.06 mmol) and thereaction mixture was heated in a sealed tube at 140° C. for 30 min. Themixture was cooled to rt, diluted with EtOAc (10 mL) and the organiclayer was washed with water (2×30 mL). The organic layer was dried overMgSO₄, filtered and concentrated under reduced pressure. The materialwas triturated with Et₂O and hexane to afford the title compound (113.0mg, 17%) as a solid. ¹H NMR (500 MHz, CDCl₃) δ 9.85-9.73 (m, 1H), 8.83(dd, J=4.3, 1.6 Hz, 2H), 7.61 (dt, J=20.0, 5.6 Hz, 2H), 7.47 (dd, J=4.3,1.6 Hz, 2H), 2.14 (s, 3H). MS (ESI) [M+H]+ 316.1/318.1.

Step 2: Preparation of1,3-dimethyl-5-[2-methyl-3-(pyridine-4-carbonyl)imidazo[1,2-a]pyridin-6-yl]pyridin-2-one

To a solution of(6-bromo-2-methyl-imidazo[1,2-a]pyridin-3-yl)-(4-pyridyl)methanone (150mg, 0.474 mmol) in a mixture of DME (5 mL) and water (0.5 mL) were added1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(prepared as in US20130053362, 141.8 mg, 0.569 mmol), Cs₂CO₃ (386.5 mg,1.19 mmol) and Pd(PPh₃)₄ (54.8 mg, 0.047 mmol). The reaction mixture wasdegassed with N₂ for 5 min and then heated in a sealed tube at 100° C.for 18 h. The mixture was cooled to rt and diluted with EtOAc (10 mL)and water (10 mL). The organic layer was separated, dried over MgSO₄,filtered and concentrated under reduced pressure. The material wastriturated with a mixture of EtOAc and hexane to afford the titlecompound (166 mg, 98%) as a solid. ¹H NMR (500 MHz, CDCl₃) δ 9.74 (dd,J=1.8, 0.8 Hz, 1H), 8.86 (d, J=4.8 Hz, 2H), 7.75 (dd, J=9.2, 0.8 Hz,1H), 7.65 (dd, J=9.2, 1.9 Hz, 1H), 7.56-7.48 (m, 4H), 3.68 (s, 3H), 3.51(d, J=5.5 Hz, 2H), 2.28 (s, 3H), 2.19 (s, 3H). MS (ESI) [M+H]⁺ 359.3.

Step 3: Preparation of Compound 56

A solution of1,3-dimethyl-5-[2-methyl-3-(pyridine-4-carbonyl)imidazo[1,2-a]pyridin-6-yl]pyridin-2-one(166.0 mg, 0.46 mmol), hydrazine hydrate (1.34 ml, 15.12 mmol) and KOH(207.9 mg, 3.7 mmol) in ethylene glycol (3 mL) was heated to 150° C. ina sealed vial for 20 h. The solution was cooled to rt and diluted withDCM (10 mL) and water (10 mL). The aqueous layer was extracted with DCM(3×10 mL). The combined organic layers were dried over Na₂SO₄, filteredand concentrated under reduced pressure. The material was purified bypreparative HPLC to afford Compound 56 (52.0 mg, 33%) as a solid. ¹H NMR(500 MHz, CDCl₃) δ 8.46 (d, J=5.4 Hz, 2H), 7.55 (d, J=9.3 Hz, 1H), 7.48(s, 1H), 7.20-7.11 (m, 3H), 6.97 (d, J=5.8 Hz, 2H), 4.22 (s, 2H), 3.52(s, 3H), 2.44 (s, 3H), 2.13 (s, 3H). MS (ESI) [M+H]⁺ 345.3.

Example 41: Biological Activity

a) In Vitro Bromodomain Inhibition

To measure activity of bromodomain inhibitors, a His-epitope tagged BRD4BD149-170 is purchased from BPS Bioscience. BRD4 binding and inhibitionis assessed by monitoring the engagement of biotinylated H4-tetraacetylpeptide (H4K5/8/12/16; AnaSpec #64989-025) with the target using theAlphaLISA technology (Perkin-Elmer). Specifically, in a 384 wellOptiPlate, BRD4 (BD1) (200 nM final) is pre-incubated with either DMSO(final 1.0% DMSO) or a compound dilution series in DMSO. All reagentsare diluted in assay buffer containing 50 mM HEPES (pH 7.4), 100 mMNaCl, 0.1% (w/v) BSA, and 0.05% (w/v) CHAPS. After a 30 minuteincubation at room temperature, H4 peptide is added (200 nM final) andthe reaction is incubated an additional 30 minutes at room temperature.Alpha streptavidin donor beads and AlphaLISA nickel chelate acceptorbeads are then added to a final concentration of 10 μg/mL each. Afterone hour, equilibration plates are read on an Envision instrument andICsos calculated using a four parameter non-linear curve fit. Theresults are shown in Table 1 (BRD4 alpha).

b) Transcription of Human C-Myc in Human Leukemic MV-4-11 Cells:

The effect of compounds on transcription of human C-Myc gene ismonitored in human B-myelomonocytic leukemia cell line MV-4-11 (fromAmerican Type Culture Collection (ATCC), Manassas, Va., USA) usingQuantiGene 2.0 assay kit (Affymetrix, Santa Clara, Calif., USA).

Typically, 8,000 MV-4-11 cells are plated in sterile 96-well plates(Costar #3598 from Fisher Scientific Canada, Ottawa, Ontario, Canada) inIscove's medium supplemented with 10% fetal bovine serum, glutamine (2mM), and penicillin (100 I.U.) and streptomycin (100 μg/mL) (all fromWisent Inc., St. Bruno, Quebec, Canada). Compounds are dissolved in DMSOat 30 mM. A series of 1:3 dilutions are first made in DMSO, and further1:100 dilutions are made in serum-containing cell culture media. Thefinal concentration of DMSO is 0.1% in cell culture media.

After cells are treated with various concentrations of test compound for4 hours, cells are lysed using Quantigene 2.0 sample processing kit (#QS0100). C-Myc mRNA is detected using a QuantiGene 2.0 assay kit (#QS0009) with gene-specific probe to human C-Myc (# SA-50182) followingthe manufacturer's recommendations. Luminescene signals are read onFlexstation II microplate reader (Molecular Devices, Sunnyvale, Calif.,USA). Percentage of inhibition of C-Myc transcription is analyzed usingEXCEL (2010 version). The results are shown in Table 1 (MV-4-11).

TABLE 1 Compound No BRD4α (IC₅₀, μM) MV-4-11 (IC₅₀, μM)  1 0.122 0.058 2 0.09946 0.0592  3 0.1432 0.0863  4 0.3125 0.2758  5 0.113 0.0939  6N/A 0.0913  7 N/A 0.0928  8 0.195 0.8444  9 0.1531 0.1523 10 0.31770.8373 11 N/A 2.7293 12 N/A 0.912 13 N/A 2.6578 14 N/A 0.508 15 N/A2.5243 16 N/A 0.0813 17 N/A 0.7583 18 N/A 0.0937 19 N/A 0.1699 20 N/A0.1118 21 N/A 0.8159 22 N/A 0.0098 23 N/A 0.0165 24 N/A 0.0322 25 N/A0.1742 26 N/A 0.4919 30 N/A 0.0249 34 N/A 0.2344 42 N/A 0.8647 43 N/A0.2534 44 N/A 0.5967 45 N/A 0.5071 46 N/A 0.1776 47 N/A 0.731 48 N/A0.5367 49 N/A 0.8514 50 N/A 2.3697 51 N/A 0.6147 52 N/A 0.8906 53 N/A0.8983 54 N/A 0.1508 55 N/A 0.0845 56 N/A 0.1533 N/A: not available

Although the invention has been illustrated and described with respectto one or more implementations, equivalent alterations and modificationswill occur to others skilled in the art upon the reading andunderstanding of this specification. In addition, while a particularfeature of the invention may have been disclosed with respect to onlyone of several implementations, such feature may be combined with one ormore other features of the other implementations as may be desired andadvantageous for any given or particular application.

Accordingly, it is understood that the examples and embodimentsdescribed herein are for illustrative purposes only and that variousmodifications or changes in light thereof will be suggested to personsskilled in the art and are to be included within the spirit and purviewof this application and scope of the appended claims. Any publication,document, patent, patent application or publication referred to hereinshould be construed as incorporated by reference each in their entiretyfor all purposes.

1. A compound of Formula I:

wherein, R¹ is a substituted or unsubstituted group selected fromC₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl,C₃-C₁₀heterocycloalkyl, C₃-C₁₀cycloalkylC₁-C₆alkyl-,C₃-C₁₀heterocycloalkylC₁-C₆alkyl-, C₆-C₁₀arylC₁-C₆alkyl-,C₅-C₁₀heteroarylC₁-C₆alkyl-, C(O)R^(a), OR^(a), NHR^(a), N(R^(a))₂,C(O)NH₂, C(O)NHR^(a), C(O)N(R^(a))₂, NHC(O)R^(a), N(R^(a))C(O)R^(a),NHC(O)NHR^(a), N(R^(a))C(O)NHR^(a), NHC(O)N(R^(a))₂,N(R^(a))C(O)N(R^(a))₂, NHSO₂R^(a), N(R^(a))SO₂R^(a), NHSO₂NHR^(a),N(R^(a))SO₂NHR^(a), NHSO₂N(R^(a))₂, N(R^(a))SO₂N(R^(a))₂, SO₂R^(a),SO₂NH₂, SO₂NHR^(a), and SO₂N(R^(a))₂; R^(a) is, independently in eachoccurrence, a substituted or unsubstituted group selected fromC₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl,C₃-C₁₀heterocycloalkyl, C₃-C₁₀cycloalkylC₁-C₆alkyl-,C₃-C₁₀heterocycloalkylC₁-C₆alkyl-, C₆-C₁₀aryl, C₅-C₁₀heteroaryl,C₆-C₁₀arylC₁-C₆alkyl-, and C₅-C₁₀heteroarylC₁-C₆alkyl-; R² is selectedfrom H, NH₂, CN or a substituted or unsubstituted group selected fromC₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl,C₃-C₁₀heterocycloalkyl, C₆-C₁₀aryl, C₅-C₁₀heteroaryl, C(O)R^(a), OR^(a),SR^(a), NHR^(a), N(R^(a))₂, C(O)NH₂, C(O)NHR^(a), C(O)N(R^(a))₂,NHC(O)R^(a), SO₂R^(a), SO₂NHR^(a), SO₂N(R^(a))₂, NHSO₂R^(a),N(R^(a))SO₂R^(a), NHSO₂NHR^(a), N(R^(a))SO₂NHR^(a), NHSO₂N(R^(a))₂, andN(R^(a))SO₂N(R^(a))₂; R³ and R⁶ are each independently H, halogen, NH₂,CN or a substituted or unsubstituted group selected from C₁-C₆alkyl,C(O)R^(a), OR^(a), NHR^(a), N(R^(a))₂, C(O)NH₂, C(O)NHR^(a),C(O)N(R^(a))₂, NHC(O)R^(a); and one of R⁴ and R⁵ is H, halogen, NH₂, CNor a substituted or unsubstituted group selected from C₁-C₆alkyl,C(O)R^(a), NH₂, NHR^(a), N(R^(a))₂, C(O)NH₂, C(O)NHR^(a), C(O)N(R^(a))₂,and NHC(O)R^(a); and the other of R⁴ and R⁵ is a group of Formula II:

wherein, R⁷ and R¹⁰ are each independently H, halogen, CN, or asubstituted or unsubstituted group selected from C₁-C₆alkyl orC₃-C₆cycloalkyl group, OC₁-C₆alkyl, OC₃-C₆cycloalkyl, SC₁-C₆alkyl,SC₃-C₆cycloalkyl, NHC₁-C₆alkyl, NHC₃-C₆cycloalkyl, N(C₁-C₆alkyl)₂,NHC(O)C₁-C₆alkyl and NHC(O)C₃-C₆cycloalkyl; R⁸ is halogen, CN, or asubstituted or unsubstituted group selected from C₁-C₆alkyl orC₃-C₆cycloalkyl group, OC₁-C₆alkyl, OC₃-C₆cycloalkyl, SC₁-C₆alkyl,SC₃-C₆cycloalkyl, NHC₁-C₆alkyl, NHC₃-C₆cycloalkyl, N(C₁-C₆alkyl)₂,NHC(O)C₁-C₆alkyl and NHC(O)C₃-C₆cycloalkyl; R⁹ is a substituted orunsubstituted C₁-C₃alkyl or C₃-C₅cycloalkyl group; X¹, X², and X³ areeach selected from a nitrogen or carbon atom, wherein when X¹, X², or X³is a nitrogen atom, then the R⁷, R⁸, or R¹⁰ attached thereto is absent,provided that at least two of X¹, X², and X³ are C; or apharmaceutically acceptable salt, solvate, ester or prodrug thereof. 2.The compound of claim 1, or a pharmaceutically acceptable salt, solvate,ester or prodrug thereof, wherein R⁴ is a group of Formula II and R⁵ isa hydrogen atom or a substituted or unsubstituted C₁-C₃ alkyl. 3.-4.(canceled)
 5. The compound of claim 1, or a pharmaceutically acceptablesalt, solvate, ester or prodrug thereof, wherein R⁵ is a group ofFormula II and R⁴ is a hydrogen atom or a substituted or unsubstitutedC₁-C₃ alkyl. 6.-7. (canceled)
 8. The compound of claim 1, wherein X¹, X²and X³ are all carbon atoms, said R⁷ and R¹⁰ are each hydrogen atoms andR⁸ is selected from C₁, CN, and a substituted or unsubstitutedC₁-C₃alkyl, C₃cycloalkyl, NHC₁-C₃alkyl, or NH(C₁-C₃alkyl)₂ group.
 9. Thecompound of claim 1, wherein X¹ is a nitrogen atom and R¹⁰ is absent, X²and X³ are carbon atoms, and R⁹ is an unsubstituted C₁-C₃alkyl orC₃-C₅cycloalkyl group or a fluorinated C₁-C₃alkyl group orC₃-C₅cycloalkyl group. 10.-12. (canceled)
 13. The compound of claim 1,wherein said R³ is H or a substituted or unsubstituted C₁-C₆alkyl groupand said R⁶ is H or a substituted or unsubstituted C₁-C₆alkyl group.14.-17. (canceled)
 18. The compound of claim 1, wherein said compound isa compound of Formula III(a) or III(b):

wherein, R¹, R², R⁷, R⁸, R⁹, and R¹⁰ are as defined in claim 1, or apharmaceutically acceptable salt, solvate, ester or prodrug thereof. 19.(canceled)
 20. The compound of claim 18, wherein R⁹ is an unsubstitutedC₁-C₃alkyl or C₃-C₅cycloalkyl group, R⁷ and R¹⁰ are each hydrogen atomsand R⁸ is selected from C₁, CN, and a substituted or unsubstitutedC₁-C₃alkyl, C₃cycloalkyl, NHC₁-C₃alkyl, or NH(C₁-C₃alkyl)₂ group.21.-22. (canceled)
 23. The compound of claim 18, wherein R⁸ and R⁹ areeach independently a methyl, ethyl, isopropyl, fluoromethyl,difluoromethyl, trifluoromethyl, cyclopropyl, or difluorocyclopropylgroup.
 24. The compound of claim 1, wherein R² is hydrogen or asubstituted or unsubstituted group selected from C₁-C₆alkyl,C₃-C₁₀cycloalkyl, or C₃-C₁₀heterocycloalkyl group.
 25. (canceled) 26.The compound of claim 1, wherein R² is hydrogen or a substituted orunsubstituted group selected from methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl,tetrahydrofuranyl, tetrahydropyranyl, dioxolanyl, piperidinyl, andpyrrolidinyl.
 27. (canceled)
 28. The compound of claim 1, wherein R² ishydrogen or methyl.
 29. The compound of claim 1, wherein R¹ is abranched or linear C₁-C₆alkyl group, unsubstituted or substituted withone or more group(s) selected from halogen, OH, NH₂, CN, or asubstituted or unsubstituted group selected from C₃-C₁₀cycloalkyl,C₃-C₁₀heterocycloalkyl, C₆-C₁₀aryl, C₅-C₁₀heteroaryl, C(O)R^(a), OR^(a),NHR^(a), N(R^(a))₂, C(O)NH₂, C(O)NHR^(a), C(O)N(R^(a))₂, NHC(O)R^(a),N(R^(a))C(O)R^(a), NHC(O)NHR^(a), N(R^(a))C(O)NHR^(a), NHC(O)N(R^(a))₂,N(R^(a))C(O)N(R^(a))₂, NHSO₂R^(a), N(R^(a))SO₂R^(a), NHSO₂NHR^(a),N(R^(a))SO₂NHR^(a), NHSO₂N(R^(a))₂, N(R^(a))SO₂N(R^(a))₂, SO₂R^(a),SO₂NH₂, SO₂NHR^(a), and SO₂N(R^(a))₂, wherein R^(a) is as defined inclaim
 1. 30.-31. (canceled)
 32. The compound of claim 1, wherein R¹ isselected from C(O)R^(a), OR^(a), NHR^(a), N(R^(a))₂, C(O)NHR^(a),C(O)N(R^(a))₂, SO₂R^(a), SO₂NHR^(a), and SO₂N(R^(a))₂, wherein R^(a) isas defined in claim
 1. 33. The compound of claim 1, wherein R¹ isselected from C(O)C₃-C₁₀heterocycloalkyl, OR^(a), NHR^(a), N(R^(a))₂,C(O)NHR^(a), SO₂(C₃-C₁₀heterocycloalkyl), and SO₂NHR^(a), wherein R^(a)is independently in each occurrence selected from a substituted orunsubstituted C₁-C₆alkyl, C₃-C₁₀cycloalkyl, C₃-C₁₀heterocycloalkyl,C₆-C₁₀aryl, or C₅-C₁₀heteroaryl.
 34. (canceled)
 35. The compound ofclaim 1, or a pharmaceutically acceptable salt, solvate, or prodrugthereof, wherein the compound is selected from


36. A pharmaceutical composition, comprising a compound of claim 1,together with a pharmaceutically acceptable carrier, diluent orexcipient. 37.-63. (canceled)
 64. A method for treating a disease orcondition for which a bromodomain inhibitor is indicated, whichcomprises administering to a subject in need thereof, a therapeuticallyeffective amount of a compound according to claim
 1. 65.-74. (canceled)75. A method for the treatment of a disease or condition selected fromauto-immune disorders, inflammatory disorders, dermal disorders, andneoplasms, which comprises administering to a subject in need thereof, atherapeutically effective amount of a compound according to claim 1.76.-78. (canceled)
 79. The method of claim 75, wherein the disease orcondition is a neoplasm selected from bladder cancer, leukemia,lymphoma, brain cancer, central nervous system cancer, breast cancer,cervix cancer, colorectal cancer, colon cancer, kidney cancer, livercancer, lung cancer, mesothelioma, ovarian cancer, pancreatic cancer,prostate cancer, skin cancer or gastric cancer. 80.-82. (canceled)